2,3-disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors

ABSTRACT

The present invention relates to novel compounds, pharmaceutical compositions containing such compounds and to their use in therapy.

FIELD OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing such compounds and to their use in therapy.

BACKGROUND OF THE INVENTION

The genomes of eukaryotic organisms are highly organised within thenucleus of the cell. The long strands of duplex DNA are wrapped aroundan octomer of histone proteins (most usually comprising two copies ofhistones H2A, H2B, H3 and H4) to form a nucleosome. This basic unit isthen further compressed by the aggregation and folding of nucleosomes toform a highly condensed chromatin structure. A range of different statesof condensation are possible, and the tightness of this structure variesduring the cell cycle, being most compact during the process of celldivision. Chromatin structure plays a critical role in regulating genetranscription, which cannot occur efficiently from highly condensedchromatin. The chromatin structure is controlled by a series of posttranslational modifications to histone proteins, notably histones H3 andH4, and most commonly within the histone tails which extend beyond thecore nucleosome structure. These modifications include acetylation,methylation, phosphorylation, ubiquitinylation, SUMOylation. Theseepigenetic marks are written and erased by specific enzymes, which placethe tags on specific residues within the histone tail, thereby formingan epigenetic code, which is then interpreted by the cell to allow genespecific regulation of chromatin structure and thereby transcription.

Histone acetylation is most usually associated with the activation ofgene transcription, as the modification loosens the interaction of theDNA and the histone octomer by changing the electrostatics. In additionto this physical change, specific proteins recognise and bind toacetylated lysine residues within histones to read the epigenetic code.Bromodomains are small (˜110 amino acid) distinct domains withinproteins that bind to acetylated lysine resides commonly but notexclusively in the context of histones. There is a family of around 50proteins known to contain bromodomains, and they have a range offunctions within the cell.

The BET family of bromodomain containing proteins comprises 4 proteins(BRD2, BRD3, BRD4 and BRDT) which contain tandem bromodomains capable ofbinding to two acetylated lysine residues in close proximity, increasingthe specificity of the interaction. Numbering from the N-terminal end ofeach BET protein the tandem bromodomains are typically labelled BindingDomain 1 (BD1) and Binding Domain 2 (BD2) (Chung et al, J Med. Chem,2011, 54, 3827-3838).

A novel class of compounds have been found which inhibit the binding ofbromodomains with its cognate acetylated proteins, more particularly aclass of compounds that inhibit the binding of BET family bromodomainsto aceylated lysine residues, even more particularly a class ofcompounds that selectively inhibit the binding and function of BETfamily bromodomains via Binding Domain 2 (BD2). Such compounds willhereafter be referred to as “bromodomain inhibitors”.

Funabashi et al describe 1,2,3,4,-tetrahydroquinolines and conduct aconfiguration and conformation analysis (Funabashi et al, Bulletin ofthe Chemical Society of Japan, 1969, 42, 2885-2894).

SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is provided a compoundof formula (I)

or a salt thereof, more particularly a compound of formula (I) or apharmaceutically acceptable salt thereof.

In a second aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers, diluents or excipients.

In a third aspect of the present invention, there is provided a compoundof formula (I), or a pharmaceutically acceptable salt thereof for use intherapy, in particular in the treatment of diseases or conditions forwhich a bromodomain inhibitor is indicated.

In a fourth aspect of the present invention, there is provided a methodof treating diseases or conditions for which a bromodomain inhibitor isindicated in a subject in need thereof which comprises administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In a fifth aspect of the present invention, there is provided the use ofa compound of formula (I), or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for the treatment of diseases orconditions for which a bromodomain inhibitor is indicated.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I)

or a salt thereofwhereinR₁ is C₁₋₄alkyl;R₂ is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CH₂CF₃, —CH₂OCH₃ or heterocyclyl;R₃ is C₁₋₄alkyl, —CH₂F, —CH₂OH or —CH₂OC(O)CH₃;R₄ when present is H, hydroxy, halo, cyano, —CO₂H, —CONH₂, —OSO₂CF₃,—C(O)N(R₈)C₁₋₄alkyleneOH, —C(O)N(R₈)C₁₋₄alkyleneOCH₃,—C(O)N(R₈)C₁₋₄alkyleneNR₆R₇, —C(O)N(R₈)C₁₋₄alkyleneSO₂CH₃,—C(O)N(R₈)C₁₋₄alkyleneCN, —C(O)NHOH, —C(O)NHCH(CH₂OH)₂, —OCH₂CH₂OH,—B—C₁₋₆alkyl, —B—C₃₋₇cycloalkyl, —B-phenyl, —B-heterocyclyl or—B-heteroaromatic, wherein the C₃₋₇cycloalkyl, phenyl, heterocyclyl orheteroaromatic ring is optionally substituted by 1 or 2 substituentsindependently selected from ═O, C₁₋₆alkyl, C₁₋₆alkoxy, halo, —NH₂,—CO₂H, —C(O)C₁₋₆alkyl, —C(O)NHC₁₋₆alkyl, cyano, —CH₂CH₂NHCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, C₃₋₇cycloalkyl, phenyl, heterocyclyl and heteroaromatic;R₅ when present is H, halo, hydroxy or C₁₋₆alkoxy;A is —NH—, —O—, —S—, —SO—, —SO₂—, —N(C₁₋₄alkyl)- or —NC(O)(CH₃)—;B is a bond, —O—, —N(R₈)—, S, —SO—, —SO₂—, —SO₂N(R₈)—, —CH₂—, —C(O)—,—CO₂—, —N(R₈)C(O)—, —C(O)N(R₈)—, —C(O)N(R₈)CH₂— or —C(O)N(R₈)CH₂CH₂—;V is phenyl, heteroaromatic or pyridone any of which may be optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₆alkyl, fluorine, chlorine, C₁₋₆alkoxy, hydroxy, cyclopropyl, cyano,—CO₂CH₃, heterocyclyl, —CO₂H, —CH₂NR₆R₇, —NR₆R₇, —C(O)NR₆R₇, —NR₆C(O)R₇,—CF₃, —NO₂, —CH₂OCH₃, —CH₂OH—, CH(OH)CH₃, —SO₂CH₃, —CH₂heterocyclyl,—OCH₂CH₂NHC(O)CH₃, —OCH₂CH₂OH, —OCH₂CH₂NH₂, —C(O)NHheteroaromatic,—C(O)NHCH₂heterocyclyl, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂CH₂NH₂,—C(O)NHCH₂CH₂SO₂Me, —C(O)NHCH₂CH(OH)CH₃, —C(O)heterocyclyl and—C(O)NHheterocyclyl, wherein the heterocyclyl ring is optionallysubstituted by —OH;R₆, R₇, R₈, R₉ and R₁₀ are each independently selected from H andC₁₋₄alkyl;

W is CH or N; X is C or N; Y is C or N; and Z is CH or N;

subject to the proviso that no more than 2 of W, X, Y and Z are N; andthat the compound of formula (I) is not1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanoneor1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one.

In one embodiment the compound of formula (I) or a salt thereof is aracemic mixture of formula (Ia)

or a salt thereof.

In another embodiment the compound of formula (I) or a salt thereof isan enantiomer of formula (Iaa)

or a salt thereof.

In one embodiment there is provided a compound of formula (I) or a saltthereof

wherein:R₁ is C₁₋₄alkyl;R₂ is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CH₂CF₃ or —CH₂OCH₃;R₃ is C₁₋₄alkyl;R₄ when present is H, hydroxy, halo, cyano, —CO₂H, —CONH₂, —OSO₂CF₃,—C(O)N(R₈)CH₂CH(R₈)OH, —C(O)N(R₈)CH₂CH₂OCH₃, —C(O)N(R₈)CH₂CH₂NHCH₃,—C(O)N(R₈)CH₂CH₂SO₂CH₃, —C(O)N(R₈)CH₂CH₂CN, —B—C₁₋₆alkyl,—B—C₃₋₇cycloalkyl, —B-phenyl, —B-heterocyclyl or —B-heteroaromatic,wherein the C₃₋₇cycloalkyl, phenyl, heterocyclyl or heteroaromatic ringis optionally substituted by 1 or 2 substituents independently selectedfrom ═O, C₁₋₆alkyl, C₁₋₆alkoxy, halo, —NH₂, —CO₂H, —C(O)NHC₁₋₆ alkyl,cyano, —CH₂CH₂NHCH₃, —CH₂CH₂OCH₃, C₃₋₇cycloalkyl, phenyl, heterocyclyland heteroaromatic;R₅ when present is H, halo, hydroxy or C₁₋₆alkoxy;A is —NH—, —O—, —S—, —SO—, —SO₂— or —N(C₁₋₄alkyl)-;B is a bond, —O—, —N(R₈)—, S, —SO—, —SO₂—, —SO₂N(R₈)—, —CH₂—, —C(O)—,—N(R₈)C(O)—, —C(O)N(R₈)—, —C(O)N(R₈)CH₂— or —C(O)N(R₈)CH₂CH₂—;V is phenyl or heteroaromatic either of which may be optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₆alkyl, fluorine, chlorine, C₁₋₆alkoxy, hydroxy, cyclopropyl, cyano,—CO₂CH₃, heterocyclyl, —CO₂H, —CH₂NR₆R₇, —NR₆R₇, —C(O)NR₆R₇ and—NR₆C(O)R₇;R₆, R₇, R₈ and R₉ are each independently selected from H and C₁₋₄alkyl;

W is CH or N; X is C or N; Y is C or N; and Z is CH or N;

subject to the proviso that no more than 2 of W, X, Y and Z are N; andthat the compound of formula (I) is not1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanoneor1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one.

In a further embodiment there is provided a compound of formula (I)

or a salt thereofwherein:R₁ is C₁₋₄alkyl;R₂ is C₁₋₄alkyl, C₃₋₇cycloakyl, —CH₂CF₃ or —CH₂OCH₃;R₃ is C₁₋₄alkyl;R₄ when present is H, hydroxy, —B—C₁₋₆alkyl, —B—C₃₋₇cycloalkyl,—B-phenyl, —B-heterocyclyl or —B-heteroaromatic, wherein theC₃₋₇cycloalkyl, phenyl, heterocyclyl or heteroaromatic ring isoptionally substituted by 1 or 2 substituents independently selectedfrom ═O, C₁₋₆alkyl, C₁₋₆alkoxy, halo, —NH₂, —CO₂H, —C(O)NHC₁₋₆alkyl,cyano, —CH₂CH₂NHCH₃, —CH₂CH₂OCH₃, C₃₋₇cycloalkyl, phenyl, heterocyclyland heteroaromatic;R₅ when present is H, halo, hydroxy or C₁₋₆alkoxy;A is —NH—, —O—, —S—, —SO—, —SO₂— or —N(C₁₋₄alkyl)-;B is a bond, —O—, —N(R₈)—, —SO₂—, —SO₂NH— or —CH₂—;V is phenyl or heteroaromatic either of which may be optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₆alkyl, fluorine, chlorine, C₁₋₆alkoxy, hydroxy, cyclopropyl, cyano,—CO₂CH₃, heterocyclyl, —NR₆R₇, —C(O)NR₆R₇ and —NR₆C(O)R₇;R₆, R₇ and R₈ are each independently selected from H and C₁₋₄alkyl;

W is CH or N; X is C or N; Y is C or N; and Z is CH or N;

subject to the proviso that no more than 2 of W, X, Y and Z are N; andthat the compound of formula (I) is not1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanoneor 1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one.

In one embodiment R₁ is methyl or ethyl. In another embodiment R₁ ismethyl.

In one embodiment R₂ is C₁₋₄alkyl, C₃₋₇cycloakyl, —CH₂CF₃ or —CH₂OCH₃.In another embodiment R₂ is methyl, ethyl or cyclopropyl. In anotherembodiment R₂ is methyl or cyclopropyl. In a further embodiment R₂ iscyclopropyl.

In one embodiment R₃ is C₁₋₄alkyl. In another embodiment R₃ is methyl.

In one embodiment R₄ is H, hydroxy, fluoro, cyano, —CO₂H, —CONH₂,—OSO₂CF₃, —C(O)NHCH₂CH₂OH, C(O)NHCH₂C(CH₃)OH, —C(O)NHCH₂CH₂OCH₃,—C(O)NHCH₂CH₂NHCH₃, —C(O)NHCH₂CH₂SO₂CH₃, —C(O)NHCH₂CH₂CN, —B—CH₃,—B—CH(CH₃)₂, —B—CH₂CH₃, —B-phenyl, —B— heterocyclyl or—B-heteroaromatic, wherein the phenyl, heterocyclyl or heteroaromaticring is optionally substituted by 1 or 2 substituents independentlyselected from ═O, —CH₃, —CH₂CH₃, —OCH₃, —NH₂, —C(O)NHCH₃, —CH₂CH₂NHCH₃,—CH₂CH₂OCH₃ and —CO₂H.

In another embodiment R₄ is H, hydroxy, fluoro, cyano, —CO₂H, —CONH₂,—OSO₂CF₃, —C(O)NHCH₂CH₂OH, C(O)NHCH₂C(CH₃)OH, —C(O)NHCH₂CH₂OCH₃,—C(O)NHCH₂CH₂NHCH₃, —C(O)NHCH₂CH₂SO₂CH₃, —C(O)NHCH₂CH₂CN, —B—CH₃,—B—CH(CH₃)₂, —B—CH₂CH₃, —B-phenyl, —B— piperidinyl, —B-morpholinyl,—B-piperazinyl, —B-2,5-diazabicyclo[2.2.2]octan-2-yl,—B-8-oxa-3-azabicyclo[3.2.1]octan-3-yl,—B-3,8-diazabicyclo[3.2.1]octan-3-yl, —B-pyrrolidinyl,—B-3,6-dihydro-2H-pyran, —B-1,2,3,6-tetrahydropyridinyl,—B-tetrahydrofuranyl, —B-tetrahydro-2H-thiopyran1,1,dioxide,—B-pyrazolyl or —B-pyridinyl wherein the phenyl, heterocyclyl orheteroaromatic ring is optionally substituted by 1 or 2 substituentsindependently selected from ═O, —CH₃, —CH₂CH₃, —OCH₃, —NH₂, —C(O)NHCH₃,—CH₂CH₂NHCH₃, —CH₂CH₂OCH₃ and —CO₂H.

In another embodiment R₄ is H, —C(O)NHCH₃, —C(O)NHCH₂CH₃,—C(O)NHCH₂CH₂OCH₃, -morpholinyl, -piperazinyl, -3,6-dihydro-2H-pyran,-1,2,3,6-tetrahydropyridinyl, -pyrazolyl, —C(O)NH-tetrahydro-2H-pyran,—C(O)NH-pyridinyl or —C(O)NH-pyrazolyl wherein the heterocyclyl orheteroaromatic ring is optionally substituted by —CH₂CH₂OCH₃.

In another embodiment R₄ is H, —C(O)NHCH₃, —C(O)NHCH₂CH₃,—C(O)NHCH₂CH₂OCH₃,

In another embodiment R₄ is selected from:

-   -   (i) —C(O)NHC₁₋₆alkyl (such as —C(O)NHCH₃, —C(O)NHCH₂CH₃, or        C(O)NHCH(CH₃)₂);    -   (ii) —C(O)N(R₈)C₁₋₄alkyleneOH (such as —C(O)NHCH₂CH₂OH,        —C(O)NHCH(CH₃)CH₂OH, C(O)NHCH₂C(CH₃)₂OH or C(O)NHCH₂CH(CH₃)OH);    -   (iii) —C(O)N(R₈)C₁₋₄alkyleneOCH₃ (such as —C(O)NHCH₂CH₂OCH₃,        C(O)NHCH₂CH₂CH₂OCH₃ or C(O)NHCH₂CH(CH₃)OCH₃);    -   (iv) —C(O)NHCH(CH₂OH)₂,    -   (v) —C(O)N(R₈)C₁₋₄alkyleneNR₆R₇ (such as C(O)NHCH₂CH₂NHCH₃ or        C(O)NHCH₂CH₂N(CH₃)₂);    -   (vi) —C(O)N(R₈)C₁₋₄alkyleneSO₂CH₃, (such as C(O)NHCH₂CH₂SO₂CH₃);    -   (vii) —C(O)N(R₈)C₁₋₄alkyleneCN (such as —C(O)NHCH₂CH₂CN); and    -   (viii) —B-heterocyclyl or —B-heteroaromatic in which B is        —C(O)NH, —C(O)NHCH₂— or —C(O)NHCH₂CH₂— (such as a group selected        from

In a further embodiment R₄ is —C(O)NH₂.

In a further embodiment R₄ is —CO₂H.

In a further embodiment R₄ is cyano.

In a further embodiment R₄ is fluoro.

In one embodiment B is a bond, —O—, —NH— —C(O)NH— or —SO₂—. In anotherembodiment B is a bond. In another embodiment B is —O—. In anotherembodiment B is —NH—. In another embodiment B is —SO₂—. In a furtherembodiment B is —C(O)NH—.

In one embodiment R₅ is H, fluoro, hydroxy or —OCH₃. In anotherembodiment R₅ is H, fluoro or —OCH₃ In a further embodiment R₅ is H.

In one embodiment A is NH, 0 or N(CH₃). In another embodiment A is NH.In another embodiment A is O. In a further embodiment A is N(CH₃).

In one embodiment V is phenyl or heteroaromatic, either of which may beoptionally substituted by 1 or 2 substituents independently selectedfrom C₁₋₆alkyl, fluorine, chlorine, —OCH₃, —OCH(CH₃)₂, hydroxy,cyclopropyl, cyano, —CO₂H, —CH₂NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, —CO₂CH₃,piperazinyl and morpholinyl.

In another embodiment V is phenyl, pyridinyl, pyrimidinyl,imidazopyridinyl, quinolinyl, thienyl, thiazolyl, oxazolyl andpyrazinyl, any of which may be optionally substituted by 1 or 2substituents independently selected from C₁₋₆alkyl, fluorine, chlorine,—OCH₃, —OCH(CH₃)₂, hydroxy, cyclopropyl, cyano, —CH₂NH₂, —C(O)NHCH₃,—CO₂CH₃, piperazinyl and morpholinyl.

In another embodiment V is phenyl or pyridinyl either of which may beoptionally substituted by 1 substituent selected from methyl, —OCH₃,fluorine, —CH₂NH₂ and cyano.

In another embodiment V is

In another embodiment V is

In another embodiment V is

In a further embodiment V is

In a further embodiment V is

In one embodiment W is CH. In another embodiment W is N.

In one embodiment X is C. In another embodiment X is N

In one embodiment Y is C. In another embodiment Y is N.

In one embodiment Z is CH. In another embodiment Y is N.

It is to be understood that the present invention covers allcombinations of substituent groups described hereinabove.

Compounds of the invention include the compounds of Examples 1 to 599and salts thereof.

Compounds of the invention include the compounds of Examples 1 to 292and salts thereof.

In another embodiment compounds of the invention include the compoundsof Examples 1 to 290 and salts thereof. In another embodiment compoundsof the invention include the compounds of Examples 293 to 599 and saltsthereof.

In one embodiment, the compound of formula (I) is

-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((6-methoxypyridin-2-yl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-(imidazo[1,2-a]pyridin-8-ylamino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((3-methoxyphenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((3-morpholinophenyl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(quinolin-5-ylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((3-(piperazin-1-yl)phenyl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((4-chloro-2-methoxyphenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2(1H)-one;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(thiophen-3-ylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((4-chlorophenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((3-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((4-methoxyphenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(m-tolylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyridin-3-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(p-tolylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((5-chloropyridin-3-yl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((2-methylpyridin-4-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(o-tolylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((4-fluorophenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-3-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((3-cyclopropylphenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((3-fluorophenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-2-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-(((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-(((2S,3R,4R)-2-cyclopropyl-4-((3-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-(((2S,3R,4R)-2-cyclopropyl-4-((6-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-isopropoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((4-cyclopropylphenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-methyl    4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((3-hydroxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinonitrile;-   rac-1-((2S,3R,4R)-2-cyclobutyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-isopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-3-methyl-4-(phenylamino)-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2R,3R,4R)-2-(methoxymethyl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1    (2H)-yl)propan-1-one;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one;-   rac-1-((2S,3S,4R)-2-cyclopropyl-3-methyl-4-(methyl(phenyl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-methoxy-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-hydroxy-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl    trifluoromethanesulfonate;-   rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-7-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-7-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-7-hydroxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(methylsulfonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(isopropylsulfonyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2,3-dimethyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2,3-dimethyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-2,3-dimethyl-6-(3-methylpiperazin-1-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-6-morpholino-4-(pyridin-3-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-(4-aminopiperidin-1-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-6-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-2,3-dimethyl-6-(2-methylmorpholino)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-6-(-2,5-diazabicyclo[2.2.2]octan-2-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-2,3-dimethyl-6-(3-methylpyrrolidin-1-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-2,3-dimethyl-6-(2-methylpyrrolidin-1-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-6-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-1-((2S,3R,4R)-2-ethyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-2-cyclopropyl-3-methyl-6-(3-methylpiperazin-1-yl)-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-((tetrahydro-2H-pyran-4-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic    acid;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1    (2H)-yl)ethanone;-   rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-4-((6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-N-methylbenzamide;-   rac-5-((6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-N-methylpicolinamide;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(6-methoxypyridin-3-yl)-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-2-cyclopropyl-3-methyl-6-(3-methylpiperazin-1-yl)-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-6-(piperazin-1-yl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-(4-aminopiperidin-1-yl)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-hydroxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-3,4-dihydro-1,7-naphthyridin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-3-methyl-4-(phenylamino)-2-propyl-3,4-dihydro-1,7-naphthyridin-1    (2H)-yl)ethanone;-   rac-1-((2S,3S,4R)-2-cyclopropyl-3-methyl-4-phenoxy-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3S,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methyloxazol-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((3-(aminomethyl)phenyl)amino)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N,N-dimethylbenzamide;-   rac-1-((2S,3R,4R)-4-((5-chloropyridin-2-yl)amino)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoic    acid;-   rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-2-methylnicotinonitrile;-   rac-2-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrimidine-5-carbonitrile;-   rac-1-((2S,3R,4R)-2,3-diethyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic    acid;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,N,3-trimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-6-fluoro-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-fluoro-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-5-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   rac-6-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-1-((2S,3R,4R)-6-fluoro-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-ethyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   4-(((2R,3S,4S)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-4-((5-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-6-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-5-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-5-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((5-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-5-(((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   rac-1-((2S,3R,4)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-6-(((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-5-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-5-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-6-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-6-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2-ethyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-ethyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   5-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   rac-5-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile;-   rac-6-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   4-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   4-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((R)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-((S)-3-methylpiperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-6-((S)-3-methylpiperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((rac-2S,3R,4R)-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   4-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide;-   6-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile;-   rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N,2,3-trimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-N,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-N,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2R,3S,4S)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic    acid;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-propyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(pyrrolidine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(morpholine-4-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(morpholine-4-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(2-morpholinoethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-((S)-tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-((R)-tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxypropyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic    acid;-   rac-(2S,3R,4R)-1-acetyl-N-(2-hydroxyethyl)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N-ethyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-N-(piperidin-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-N-(2-(methylamino)ethyl)-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N-(2-methoxyethyl)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N-(2-cyanoethyl)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-N-(2-morpholinoethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N-isopropyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-(morpholine-4-carbonyl)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   (rac-2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-N-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic    acid;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-N-(2-hydroxyethyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N,2-diethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(piperidin-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-N-(2-(methylamino)ethyl)-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-N-(2-methoxyethyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N-(2-cyanoethyl)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(2-morpholinoethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-N-isopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-(2S,3R,4R)-1-acetyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(morpholine-4-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   (rac-2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylthiazol-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic    acid; or a salt thereof.

In another embodiment, the compound of formula (I) is

-   (2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile;-   (2S,3R,4R)-1-Acetyl-2-cyclopropyl-4-((6-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile;-   2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinamide;-   (2S,3R,4R)-1-Acetyl-4-((3-(2-aminoethoxy)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile;-   (2S,3R,4R)-1-acetyl-4-((4-cyano-2-fluorophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-N-(oxetan-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxyethyl)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-N-(oxetan-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-N-(2-methoxyethyl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-N-(oxetan-3-yl)-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxypropyl)-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   rac-4-(((2S,3R,4R)-1-acetyl-6-(4-acetylpiperazin-1-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile;-   rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone;-   1-((2S,3R,4R)-2-ethyl-3-methyl-6-(piperazin-1-yl)-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1    (2H)-yl)ethanone;    or a salt thereof.

In another embodiment the compound of formula (I) is:

-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic    acid or a salt thereof.

In a further embodiment the compound of formula (I) is:

-   (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide    or a salt thereof.

The term “C₁₋₆alkyl” as used herein refers to a straight or branchedalkyl containing at least 1, and at most 6, carbon atoms. Examples of“C₁₋₆alkyl” as used herein include, but are not limited to, methyl,ethyl, n-propyl, n-butyl, isobutyl, isopropyl, t-butyl, pentyl andhexyl.

The term “C₁₋₄alkyl” refers to a straight or branched alkyl containingat least 1, and at most 4, carbon atoms. Examples of “C₁₋₄alkyl” as usedherein include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, isobutyl, isopropyl and t-butyl.

The term “C₁₋₄alkylene” means a straight or branched saturated alkylchain containing at least one, and at most four, carbon atoms. Examplesof “C₁₋₄alkylene” as used herein include, but are not limited to,methylene, ethylene, propylene and butylene.

The term “C₃₋₇cycloalkyl” as used herein refers to a saturated orunsaturated non-aromatic carbocyclic ring containing at least 3 and atmost 7 carbon atoms. Examples of C₃₋₇cycloalkyl groups include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl and cyclohexenyl.

The term “C₁₋₆alkoxy” as used herein refers to a straight or branchedalkoxy group containing at least 1, and at most 6, carbon atoms.Examples of “C₁₋₆alkyloxy” groups as used herein include, but are notlimited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy,2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.

The term “heterocyclyl” as used herein refers to a cyclic groupcontaining 4 to 10, for example 5 to 10, ring-atoms including 1, 2, 3 or4 hetero-atoms independently selected from nitrogen, oxygen and sulphur;wherein said cyclic group is saturated or unsaturated but is notaromatic. This definition includes bicyclic structures provided themoiety is non-aromatic. The point of attachment to the rest of themolecule may be by any suitable carbon or nitrogen atom. Examples ofheterocyclyls include, but are not limited to, oxetanyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl,pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, morpholinyl,thiomorpholinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl,pyranyl, dihydropyranyl, tetrahydropyranyl, piperazinyl, dioxanyl,dioxolanyl, 3,6-dihydro-2H-pyranyl, 1,2,3,6-tetrahydropyridinyl,2,5-diazabicyclo[2.2.2]octan-2-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl,3,8-diazabicyclo[3.2.1]octan-3-yl and tetrahydro-2H-thiopyran1,1-dioxide.

The term “heteroaromatic” as used herein refers to an aromatic cyclicgroup containing 5 to 10 ring-atoms including 1, 2, 3 or 4 hetero-atomsindependently selected from nitrogen, oxygen and sulphur. Thisdefinition includes bicyclic structures at least a portion of which isaromatic. The point of attachment to the rest of the molecule may be byany suitable carbon or nitrogen atom. Examples of heteroaromatic groupsinclude, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, triazinyl,pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl,pyrazolyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolinyl, naphthridinyl, quinoxalinyl, quinazolinyl,cinnolinyl, isoquinolinyl imidazopyridinyl and imidazo[1,2-a]pyridinyl.

The term “halo” as used herein refers to fluoro, chloro, bromo or iodo.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, orother problem or complication, commensurate with a reasonablebenefit/risk ratio.

The term “rac” as used herein refers to the racemic mixture of thecompounds of formula (I). For example, “rac-(2S,3R,4R)” means a racemicmixture of the (2S,3R,4R) enantiomer and the (2R,3S,4S) enantiomer.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Unless otherwise noted,all starting materials were obtained from commercial suppliers and usedwithout further purification.

The compounds of formula (I) contain at least 3 chiral atoms such thatoptical isomers, e.g. enantiomers may be formed. Accordingly, thepresent invention encompasses all isomers of the compounds of formula(I) whether as individual isomers isolated such as to be substantiallyfree of the other isomer (i.e. pure) or as mixtures (i.e. racemates andracemic mixtures). An individual isomer isolated such as to besubstantially free of the other isomer (i.e. pure) may be isolated suchthat less than 10%, particularly less than about 1%, for example lessthan about 0.1% of the other isomer is present.

Separation of isomers may be achieved by conventional techniques knownto those skilled in the art, e.g. by fractional crystallisation,chromatography or HPLC.

It will be appreciated that, for compounds of formula (I) tautomers maybe observed, for example when V is pyridinyl substituted by hydroxy. Anycomment relating to the biological activity of a tautomer should betaken to include both tautomers.

It will be further appreciated that the present invention coverscompounds of formula (I) as the free base and as salts thereof, forexample as a pharmaceutically acceptable salt thereof. In one embodimentthe invention relates to compounds of formula (I) in the form of a freebase. In one embodiment the invention relates to compounds of formula(I) or a pharmaceutically acceptable salt thereof.

Because of their potential use in medicine, salts of the compounds offormula (I) are desirably pharmaceutically acceptable. Suitablepharmaceutically acceptable salts can include acid addition salts. For areview of suitable pharmaceutically acceptable salts see Berge et al.,J. Pharm. Sci., 66:1-19, (1977). Typically, a pharmaceuticallyacceptable salt may be readily prepared by using a desired acid or baseas appropriate. The resultant salt may precipitate from solution and becollected by filtration or may be recovered by evaporation of thesolvent.

A pharmaceutically acceptable acid addition salt can be formed byreaction of a compound of formula (I) with a suitable inorganic ororganic acid (such as hydrobromic, hydrochloric, sulphuric, nitric,phosphoric, succinic, maleic, acetic, propionic, fumaric, citric,tartaric, lactic, benzoic, salicylic, aspartic, p-toluenesulphonic,benzenesulphonic, methanesulphonic, ethanesulphonic,naphthalenesulphonic such as 2-naphthalenesulphonic, or hexanoic acid),optionally in a suitable solvent such as an organic solvent, to give thesalt which is usually isolated for example by crystallisation andfiltration or by evaporation followed by trituration. A pharmaceuticallyacceptable acid addition salt of a compound of formula (I) can compriseor be for example a hydrobromide, hydrochloride, sulfate, nitrate,phosphate, succinate, maleate, acetate, propionate, fumarate, citrate,tartrate, lactate, benzoate, salicylate, glutamate, aspartate,p-toluenesulphonate, benzenesulphonate, methanesulphonate,ethanesulphonate, naphthalenesulphonate (e.g. 2-naphthalenesulphonate)or hexanoate salt.

Other non-pharmaceutically acceptable salts, e.g. formates, oxalates ortrifluoroacetates, may be used, for example in the isolation of thecompounds of formula (I), and are included within the scope of thisinvention.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).

It will be appreciated that many organic compounds can form complexeswith solvents in which they are reacted or from which they areprecipitated or crystallised. These complexes are known as “solvates”.For example, a complex with water is known as a “hydrate”. Solvents withhigh boiling points and/or capable of forming hydrogen bonds such aswater, xylene, N-methyl pyrrolidinone, methanol and ethanol may be usedto form solvates. Methods for identification of solvates include, butare not limited to, NMR and microanalysis. Solvates of the compounds offormula (I) are within the scope of the invention.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the solvates of the compounds of formula(I).

The invention encompasses all prodrugs, of the compound of formula (I)or a pharmaceutically acceptable salt thereof, which upon administrationto the recipient is capable of providing (directly or indirectly) thecompound of formula (I) or a pharmaceutically acceptable salt thereof,or an active metabolite or residue thereof. Such derivatives arerecognisable to those skilled in the art, without undue experimentation.Nevertheless, reference is made to the teaching of Burger's MedicinalChemistry and Drug Discovery, 5^(th) Edition, Vol 1: Principles andPractice, which is incorporated herein by reference to the extent ofteaching such derivatives.

The compounds of formula (I) may be in crystalline or amorphous form.Furthermore, some of the crystalline forms of the compounds of formula(I) may exist as polymorphs, which are included within the scope of thepresent invention. Polymorphic forms of compounds of formula (I) may becharacterized and differentiated using a number of conventionalanalytical techniques, including, but not limited to, X-ray powderdiffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra,differential scanning calorimetry (DSC), thermogravimetric analysis(TGA) and solid state nuclear magnetic resonance (SSNMR).

It will be appreciated from the foregoing that included within the scopeof the invention are solvates, isomers and polymorphic forms of thecompounds of formula (I) and salts thereof.

The compounds of formula (I) or salts thereof may be made by a varietyof methods, including standard chemistry. Illustrative general syntheticmethods are set out below and then specific compounds of formula (I) andpharmaceutically acceptable salts thereof, are prepared in the Examples.

Compounds of formula (I) may be prepared as described in any of theSchemes below:

wherein R₁, R₂, R₄, R₅, V, W, X, Y and Z are as defined for a compoundof formula (I); Hal is chlorine, bromine of iodine. If V or R₄ comprisea free amine, this will be protected by a suitable protecting group suchas BOC, FMOC, Cbz or benzyl, which is removed in Step 6 of thesynthesis.

In respect of steps shown in Scheme 1 the following reactions conditionsmay be utilised.

Step 1 may be carried out by treating with a suitable reagent such asDIAD, in the presence of a triphenylphosphine, in a suitable solvent,such as THF, at a suitable temperature, such as −78° C., for a period offor example 16 hours.

Step 2 may be carried out with a suitable acid catalyst, such asP(OPh)₂(O)OH, TFA or Yb(OTf)₃, in a suitable aprotic solvent, such asDCM, DCE, chloroform, THE or diethylether, at a suitable temperature,such as 0° C., for a period of for example 16 hours.

Step 3 may be carried out in the presence of a suitable base, such aspyridine, DIPEA or triethylamine, optionally in combination with DMAP,in a suitable aprotic solvent, such as DCM, DCE, chloroform, THE ordiethylether, at a suitable temperature such as 21° C., for a period of,for example, 1 hour.

Step 4 is a hydrogenation step which may be carried out in the presenceof Pd/C and H₂ or ammonium formate (transfer hydrogenation) in asuitable solvent, such as methanol, ethanol or EtOAc, at a suitabletemperature such as 21° C., for a period of, for example, 3 hours.

Step 5 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos orBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 6a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 6b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 6c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₅, V, W, X, Y and Z are as defined for a compoundof formula (I). R₁₀ is benzyl or t-butyl. R₄ is —NHR₉, N(C₁₋₆alkyl)-R₉or a heteroaromatic or heterocyclyl ring containing at least onenitrogen atom. R₉ is C₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl, heterocyclyl orheteroaromatic. Hal is chlorine, bromine or iodine.

If V or R₄ comprise a free amine, this will be protected by a suitableprotecting group such as BOC, FMOC, Cbz or benzyl, which is removed inStep 4 of the synthesis.

In respect of steps shown in Scheme 2 the following reactions conditionsmay be utilised.

Step 1 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos orBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 2 in some cases this step is not required to remove thecarboxybenzyl protecting group and the compound of formula (IIIa) isconverted directly into a compound of formula (IIb). Step 2 is ahydrogenation step which may be carried out in the presence of Pd/C andH₂ or ammonium formate (transfer hydrogenation) in a suitable solvent,such as methanol, ethanol or EtOAc, at a suitable temperature such as21° C., for a period of, for example, 3 hours.

Step 3 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos orBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 4a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 4b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 4c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₅, V, W, X, Y and Z are as defined for a compoundof formula (I). R₈ is C₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl, heterocyclyl orheteroaromatic. Hal is chlorine, bromine or iodine. If V comprises afree amine, it will be protected by a suitable protecting group such asBOC, FMOC, Cbz or benzyl, which is removed in Step 4 of the synthesis.

In respect of steps shown in Scheme 3 the following reactions conditionsmay be utilised.

Step 1 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand, if required, such as BrettPhos, DavePhos, XantPhos, X-Phos orBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₂CO₃, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour,followed by oxidation with a suitable oxidising agent, such as mCPBA,H₂O₂, or KMnO₄/MnO₂, in a suitable solvent, such as toluene, THE or DCM,at a suitable temperature, such as 21° C., for a suitable period, suchas 3 hours.

Step 2 is a hydrogenation step which may be carried out in the presenceof Pd/C and H₂ or ammonium formate (transfer hydrogenation) in asuitable solvent, such as methanol, ethanol or EtOAc, at a suitabletemperature such as 21° C., for a period of, for example, 3 hours.

Step 3 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos andBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₂CO₃, in asuitable solvent, such as toluene, THE or 1, 4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 4a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 4b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 4c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I). Hal is chlorine, bromine or iodine. If V or R₄comprise a free amine, this will be protected by a suitable protectinggroup such as BOC, FMOC, Cbz or benzyl which is removed in Step 7 of thesynthesis. R is selected from —B(OH)₂, —BF₃K and

In respect of steps shown in Scheme 4 the following reactions conditionsmay be utilised.

Step 1 may be carried out in the presence of a suitable rhodium catalystsuch as tris(triphenylphosphine)rhodium(1)carbonyl hydride, in asuitable solvent, such as THF, at a suitable temperature, such as 80°C., for a period of for example 2 hours.

Step 2 may be carried out with a suitable acid catalyst, suchP(OPh)₂(O)OH, TFA or Yb(OTf)₃, in a suitable aprotic solvent, such asDCM, DCE, chloroform, THE or diethylether, at a suitable temperature,such as 0° C., for a period of for example 16 hours.

Step 3 may be carried out in the presence of a suitable base, such aspyridine, DIPEA or triethylamine, optionally in combination with DMAP,in a suitable aprotic solvent, such as DCM, DCE, chloroform, THE ordiethylether, at a suitable temperature such as 21° C., for a period of,for example, 16 hours.

Step 4 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos orBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 5 may be carried out with a suitable acid, such as HCl in1,4-dioxane or TFA in DCM, at a suitable temperature, such as 21° C.,for a suitable period, for example 1 hour.

Step 6 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos andBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₂CO₃, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 7a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 7b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 7c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I). Hal is fluorine or chlorine. If V or R₄comprise a free amine, this will be protected by a suitable protectinggroup such as BOC, FMOC, Cbz or benzyl which is removed in the Step 4 ofthe synthesis.

In respect of steps shown in Scheme 5 the following reactions conditionsmay be utilised.

Step 1 may be carried out by treating with AcOH and a suitable nitritesuch as NaNO₂, in a suitable solvent, such as water, at a suitabletemperature, such as 21° C., for a period of for example 1 hour.

Step 2 may be carried out with a suitable metal hydroxide such as LiOHor NaOH in an aqueous solvent such as water, methanol, ethanol or THF,at a suitable temperature, such as 21° C., for a period of for example 1hour.

Step 3 may be carried out in the presence of a suitable strong base,such as NaO^(t)Bu, NaH, BuLi or LDA, in a suitable solvent, such as DMF,THE or 1,4-dioxane, at a suitable temperature such as 70° C., for aperiod of, for example, 2 hours.

Step 4a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 4b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 4c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I). If V or R₄ comprise a free amine, this will beprotected by a suitable protecting group such as BOC, FMOC, Cbz orbenzyl which is removed in step 2 of the synthesis.

In respect of steps shown in Scheme 6 the following reactions conditionsmay be utilised.

Step 1 may be carried out by treating with DIAD and PPh₃, in a suitablesolvent, such as THE or diethylether, at a suitable temperature, such as21° C., for a period of for example 18 hours.

Step 2a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 2b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 2c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₅, V, W, Y and Z are as defined for a compound offormula (I).

In respect of steps shown in Scheme 7 the following reactions conditionsmay be utilised.

Step 1 may be carried out by treating with a demethylating agent such asBBr₃, HBr or TMSCl/NaI, in a suitable solvent, such as MeCN or DCM, at asuitable temperature, such as 0° C., for a period of for example 3hours.

Step 2 may be carried out by treating with a triflating agent such asN,N-bis(trifluoromethylsulfonyl)aniline, Comins' reagent, or Tf₂O,optionally in the presence of a base, such as NaOtBu, NaOMe, or NaOEt,and optionally in the presence of DMAP, in a suitable aprotic solvent,such as DCM, THF, toluene or DMF, at a suitable temperature, such as 0°C., for a period of for example 4 hours.

wherein R₁, R₂, R₃, R₄, V, W, X and Z are as defined for a compound offormula (I).

In respect of steps shown in Scheme 8 the following reactions conditionsmay be utilised.

Step 1 may be carried out by treating with a demethylating agent such asBBr₃, HBr or TMSCl/NaI, in a suitable solvent, such as MeCN or DCM, at asuitable temperature, such as 0° C., for a period of for example 3hours.

Step 2 may be carried out by treating with a triflating agent such asN,N-bis(trifluoromethylsulfonyl)aniline, Comins' reagent, or Tf₂O, inthe presence of a base, such as NaO^(t)Bu, NaOMe, or NaOEt, adoptionally in the presence of DMAP, in a suitable aprotic solvent, suchas DCM, THF, toluene or DMF, at a suitable temperature, such as 0° C.,for a period of, for example, 4 hours.

wherein R₁, R₂, R₃, R₅, V, W, X, Y and Z are as defined for a compoundof formula (I). R₄ is —NHR₉, N(C₁₋₆alkyl)-R₉ or a heteroaromatic orheterocyclyl ring containing at least one nitrogen atom. R₉ is C₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl, heterocyclyl or heteroaromatic. If V orR₄ comprise a free amine, this will be protected by a suitableprotecting group such as BOC, FMOC, Cbz or benzyl which is removed inthe last step of the synthesis. R is selected from —B(OH)₂, —BF₃K and

In respect of steps shown in Scheme 9 the following reactions conditionsmay be utilised.

Step 1 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos orBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 2 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos orBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 3a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 3b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 3c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₄ and V are as defined for a compound of formula(I). Hal is fluorine, chlorine, bromine or iodine. R₁₀ is benzyl ort-butyl. If V or R₄ comprise a free amine, this will be protected by asuitable protecting group such as BOC, FMOC, Cbz or benzyl which isremoved in step 6 of the synthesis.

In respect of steps shown in Scheme 10 the following reactionsconditions may be utilised.

Step 1 may be carried out with a suitable acid catalyst, suchP(OPh)₂(O)OH, TFA or Yb(OTf)₃, in a suitable aprotic solvent, such asDCM, DCE, chloroform, THE or diethylether, at a suitable temperature,such as 60° C., for a period of for example 18 hours.

Step 2 may be carried out in the presence of a suitable base, such aspyridine, DIPEA or triethylamine, optionally in combination with DMAP,in a suitable aprotic solvent, such as DCM, DCE, chloroform, THE ordiethylether, at a suitable temperature such as 21° C., for a period of,for example, 4 hours.

Step 3 may be carried out by treating with a triflating agent such asTf₂O, Comin's reagent, or N,N-bis(trifluoromethylsulfonyl)anilineoptionally in the presence of DMAP, in a suitable aprotic solvent, suchas DCM, THF, toluene or DMF, at a suitable temperature, such as 0° C.,for a period of for example 3 hour.

Step 4a is a hydrogenation step which may be carried out in the presenceof Pd/C and H₂ or ammonium formate (transfer hydrogenation) in asuitable solvent, such as methanol, ethanol or EtOAc, at a suitabletemperature such as 50° C., for a period of, for example, 1 hour.

Step 4b may be carried out with a suitable acid, such as HCl in1,4-dioxane or TFA in DCM, at a suitable temperature, such as 21° C.,for a suitable period, for example 1 hour

Step 5 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos andBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 6a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 6b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 6c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₅ and V are as defined for a compound of formula(I). R₁₀ is benzyl or t-butyl. Hal is fluorine, chlorine, bromine oriodine. If V comprises a free amine, this will be protected by asuitable protecting group such as BOC, FMOC, Cbz or benzyl, which isremoved in the last step of the synthesis.

In respect of steps shown in Scheme 11 the following reactionsconditions may be utilised.

Step 1a is a hydrogenation step which may be carried out in the presenceof Pd/C and H₂ in a suitable solvent, such as methanol, ethanol orEtOAc, at a suitable temperature such as 21° C., for a period of, forexample, 72 hours.

Step 1b may be carried out with a suitable acid, such as HCl in1,4-dioxane or TFA in DCM, at a suitable temperature, such as 21° C.,for a suitable period, for example 1 hour

Step 2 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos andBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour.

Step 3 may be carried out by treating with a demethylating agent such asBBr₃, HBr or TMSCl/NaI, in a suitable solvent, such as MeCN or DCM, at asuitable temperature, such as 55° C., for a period of for example 3hours.

Step 4 may be carried out by treating with a triflating agent such asComin's reagent, N,N-bis(trifluoromethylsulfonyl)aniline, or Tf₂O,optionally in the presence of DMAP, in a suitable aprotic solvent, suchas DCM, THF, toluene or DMF, at a suitable temperature, such as 21° C.,for a period of for example 1 hour.

Step 5 may be carried out with a suitable palladium catalyst, such asPdCl₂(dppf), PdCl₂ (PPh₃)₂, or Pd(PPh₃)₂ a suitable base, such astriethylamine or ammonia, a suitable acid such as formic acid in asuitable solvent, such as DMF, methanol or 1,4-dioxane at a suitabletemperature, such as 60° C., for a suitable period, such as 1 hour.

Step 6a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 6b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 6c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₃, R₄, R₅, V, W, X, Y and Z are as defined for a compoundof formula (I). If V or R₄ comprise a free amine, this will be protectedby a suitable protecting group such as BOC, FMOC, Cbz or benzyl, whichis removed in Step 3 of the synthesis.

In respect of steps shown in Scheme 12 the following reactionsconditions may be utilised.

Step 1 may be carried out by treating with a demethylating agent such asTBAF or Selectfluor, TMSCl/KF, in a suitable solvent, such as THF, MeCN,or DMF, at a suitable temperature, such as 21° C., for a period of forexample 1 hour.

Step 2 may be carried out by treating with a methylating agent such asMel, in a suitable solvent, such as THF, DMF, or toluene, in thepresence of a strong base such as NaH, BuLi or LDA, at a suitabletemperature, such as 0° C., for a period of for example 5 hours.

Step 3a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 3b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 3c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I). R₁₁ is C₁₋₄ alkyl. If V or R₄ comprise a freeamine, this will be protected by a suitable protecting group such asBOC, FMOC, Cbz or benzyl, which is removed in Step 5 of the synthesis.

In respect of steps shown in Scheme 13 the following reactionsconditions may be utilised.

Step 1 may be carried out in the presence of a base, such as KOH, NaOH,or K₂CO₃, in a suitable aprotic solvent, such as MeCN, DMF or THF, at asuitable temperature, such as 50° C., for a period of for example 7hours.

Step 2 may be carried out in the presence of a rhodium catalyst, such as(PPh₃)₃Rh(CO)H, in a suitable aprotic solvent, such as DCM, THE ortoluene, at a suitable temperature such as 60° C., for a period of, forexample, 2 hours.

Step 3 may be carried out with a suitable acid catalyst, suchP(OPh)₂(O)OH, TFA or Yb(OTf)₃, in a suitable aprotic solvent, such asDCM, DCE, chloroform, THE or diethylether, at a suitable temperature,such as −78° C., for a period of for example 5 hours.

Step 4 may be carried out in the presence of a suitable base, such aspyridine, DIPEA or tiethylamine, optionally in combination with DMAP, ina suitable aprotic solvent, such as DCM, DCE, chloroform, THE ordiethylether, at a suitable temperature such as 21° C., for a period of,for example, 1 hour.

Step 5a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 5b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 5c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I). If V or R₄ comprise a free amine, this will beprotected by a suitable protecting group such as BOC, FMOC, Cbz orbenzyl, which is removed in Step 5 of the synthesis.

In respect of steps shown in Scheme 14 the following reactionsconditions may be utilised.

Step 1 may be carried out with a suitable acid catalyst, suchP(OPh)₂(O)OH, TFA or Yb(OTf)₃, in a suitable aprotic solvent, such asDCM, DCE, chloroform, THE or diethylether, at a suitable temperature,such as 0° C., for a period of for example 16 hour.

Step 2 may be carried out in the presence of a suitable base, such aspyridine, DIPEA or tiethylamine, optionally in combination with DMAP, ina suitable aprotic solvent, such as DCM, DCE, chloroform, THE ordiethylether, at a suitable temperature such as 21° C., for a period of,for example, 3 hours.

Step 3 may be carried out by treating with an oxidising agent such asmCPBA, H₂O₂, or KMnO₄/MnO₂, in a suitable solvent, such as DCM, toluene,or THF, at a suitable temperature, such as 21° C., for a period of forexample 1 hour.

Step 4 may be carried out by treating with an oxidising agent such asmCPBA, H₂O₂, or KMnO₄/MnO₂, in a suitable solvent, such as DCM, toluene,or THF, at a suitable temperature, such as 21° C., for a period of forexample 1 hour.

Step 5a (wherein the protecting group is BOC) may be carried out with asuitable acid, such as HCl in 1,4-dioxane or TFA in DCM, at a suitabletemperature, such as 21° C., for a suitable period, for example 1 hour.

Step 5b (wherein the protecting group is FMOC) may be carried out with apiperidine solution, at a suitable temperature, such as roomtemperature, for a suitable period, for example 1 hour.

Step 5c (wherein the protecting group is Cbz or benzyl) may be carriedout by hydrogenation in the presence of Pd/C and H₂ in a suitablesolvent, such as methanol, ethanol or water, at a suitable temperaturesuch as 21° C., for a period of, for example, 16 hours.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I). Hal is chlorine, bromine or iodine. R₈ is anappropriate amine; If V or R₈ comprise a free amine, this will beprotected by a suitable protecting group such as BOC, FMOC, Cbz orbenzyl, which is removed Step 4 of the synthesis.

In respect of steps shown in Scheme 1 the following reactions conditionsmay be utilised.

Step 1 is a hydrogenation step which may be carried out in the presenceof Pd/C and H₂ in a suitable solvent, such as methanol, ethanol orEtOAc, at a suitable temperature such as 21° C., for a period of, forexample, 4 hours.

Step 2 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos andBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a suitable period, such as 1 hour; oralternatively under heating in a suitable solvent, such as NMP, DMSO, orDMF, in the presence of a suitable base, such as DIPEA, triethylamine orpyridine, at an appropriate temperature, for example 150° C., for aperiod of, for example, 30 min.

Step 3 is an amide bond forming process which may be carried out byactivating the acid as an acid chloride by reaction with a suitablechlorinating agent, such as thionyl chloride, oxalyl chloride or POCl₃,in a suitable solvent, such as DCM, chloroform or DCE at an appropriatetemperature, for example 0° C.; or by reaction with a suitableactivating group, such as HATU, COMU or DCC, in an appropriate solvent,such as DMF, THE or DCM, in the presence of a suitable base, for exampleDIPEA, triethylamine or pyridine, at an appropriate temperature, such as21° C., for a period of, for example, 90 min.

Step 4 may be carried out with a suitable acid, such as HCl in1,4-dioxane or TFA in DCM, at a suitable temperature, such as 21° C.,for a suitable period, for example 1 hour.

Step 5 is a hydrolysis step and may be carried out in the presence of anaqueous hydroxide, such as LiOH, NaOH or KOH, in an appropriate solvent,for example THF, DMF or ethanol, at an appropriate temperature, forexample 21° C., for a period of, for example, 2.5 hours.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I). Hal is chlorine, bromine or iodine. R₈ is anappropriate amine; If V or R₈ comprise a free amine, this will beprotected by a suitable protecting group such as BOC, FMOC, Cbz orbenzyl, which is removed in Step 5 of the synthesis.

In respect of steps shown in Scheme 16 the following reactionsconditions may be utilised.

Step 1 may be carried out with chlorosulfonic acid, in a suitableaprotic solvent, such as DCM, DCE or chloroform, at a suitabletemperature, such as 0° C., for a period of for example 16 hours.

Step 2 may be carried out in the presence of a suitable base, such aspyridine, DIPEA or tiethylamine, in a suitable aprotic solvent, such asDCM, DCE or chloroform, at a suitable temperature such as 21° C., for aperiod of, for example 3 hours.

Step 3 is a hydrogenation step which may be carried out in the presenceof Pd/C and H₂ in a suitable solvent, such as methanol, ethanol orEtOAc, at a suitable temperature such as 21° C., for a period of, forexample 4 hours.

Step 4 may be carried out with a suitable palladium catalyst, such asPd₂(dba)₃, PdCl₂(dppf), Pd(OAc)₂ or Pd(PPh₃)₄, a suitable phosphineligand if required, such as BrettPhos, DavePhos, XantPhos, X-Phos andBINAP, a suitable base, such as NaO^(t)Bu, Cs₂CO₃ or K₃PO₄, in asuitable solvent, such as toluene, THE or 1,4-dioxane, at a suitabletemperature, such as 100° C., for a period of, for example 1 hour.

Step 5 may be carried out with a suitable acid, such as HCl in1,4-dioxane or TFA in DCM, at a suitable temperature, such as 21° C.,for a period of, for example 1 hour.

wherein R₁, R₂, R₃, R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I).

In respect of steps shown in Scheme 17 the following reactionsconditions may be utilised.

Step 1 may be carried out by reacting with cyanogen bromide and1-hydroxypropan-2-one in the presence of an appropriate base, such asNa₂CO₃, K₂CO₃ or Cs₂CO₃, in a suitable solvent, such as THF,diethylether or 1,4-dioxane, at a suitable temperature, such as −20° C.,for a period of, for example 20 hours.

Step 2 may be carried out by reacting with benzoyl isothiocyanate in asuitable solvent, such as DCM, chloroform or DCE at a suitabletemperature, such as 21° C., for a suitable period, such as 16 hours;followed by reaction in the presence of an appropriate base, such asK₂CO₃, Na₂CO₃ or Cs₂CO₃, in a suitable solvent, such as methanol, THEand water, at a suitable temperature, such as 21° C., for a period of,for example 4 hours.

Step 3 may be carried out by reacting with 1-chloropropan-2-one in thepresence of a suitable acid, such as HCl, H₂SO₄ or HBr, in a suitablesolvent, such as ethanol, methanol or IPA, at a suitable temperature,such as 80° C., for a period of, for example 2 hours.

wherein R₁, R₂, R₃ R₄, R₅, V, W, X, Y and Z are as defined for acompound of formula (I).

In respect of steps shown in Scheme 18 the following reactionsconditions may be utilised.

Step 1 may be carried out with a suitable chiral acid catalyst, such as(11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a literature reference see JACS, 2011, 133, 14804), in asuitable aprotic solvent, such as DCM, DCE, chloroform, THE ordiethylether, at a suitable temperature, such as 0° C., for a period of,for example 40 hours.

Thus, in one embodiment the invention provides a process for preparing acompound of formula (I) comprising reacting a compound of formula (II)

wherein R₁ R₂, R₃, R₄, R₅, W, X, Y and Z are as defined above, with acompound of formula (VIII)

V-Hal  (VIII)

wherein V is as defined above and Hal is fluorine, chlorine, bromine oriodine, in the presence of a catalyst, a phosphine ligand and a base;optionally followed by a deprotection step if required. In oneembodiment the catalyst is Pd₂(dba)₃. In one embodiment the base issodium tert-butoxide. In one embodiment the phosphine ligand isDavePhoss or BrettPhos.

In another embodiment the invention provides a process for preparing acompound of formula (I) comprising reacting a compound of formula (XXIV)

wherein R₁ R₂, R₃, R₅, V, W, Y and Z are as defined above, with acompound of formula (XXXIV)

H—R₄  (XXXIV)

wherein R₄ is —NHR₉, N(C₁₋₆alkyl)-R₉ or a heteroaromatic or heterocyclylring containing at least one nitrogen atom; and R₉ is C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, heterocyclyl or heteroaromatic, in the presenceof a suitable catalyst and a phosphine ligand; optionally followed by adeprotection step if required. In one embodiment the catalyst isPd₂(dba)₃. In one embodiment the phosphine ligand is BINAP.

In another embodiment the invention provides a process for preparing acompound of formula (I) comprising reacting a compound of formula (XXIV)

wherein R₁ R₂, R₃, R₅, V, W, Y and Z are as defined above, with acompound of formula (XXXV)

R—R₄  (XXXV)

wherein R₄ is —NHR₉, N(C₁₋₆alkyl)-R₉ or a heteroaromatic or heterocyclylring containing at least one nitrogen atom; R₉ is C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, heterocyclyl or heteroaromatic; and R isselected from —B(OH)₂, —BF₃K and

optionally followed by a deprotection step if required.

In another embodiment the invention provides a process for preparing acompound of formula (I) comprising reacting a compound of formula (XXI)

wherein R₁ R₂, R₃, R₄, R₅, W, X, Y and Z are as defined above, with acompound of formula (VIIIb)

X—V  (VIIIb)

wherein V is as defined above and X is fluorine or hydroxide; optionallyfollowed by a deprotection step if required.

In another embodiment the invention provides a process for preparing acompound of formula (II) comprising hydrogenation of a compound offormula (III)

wherein R₁, R₂, R₃, R₄, R₅, R₁₀, W, X, Y and Z are as defined above.

In another embodiment the invention provides a process for preparing acompound of formula (XXI) wherein R₁₀ is t-butyl, comprising reacting acompound of formula (XX)

wherein R₁ R₂, R₃, R₄, R₅, W, X, Y and Z are as defined above, with abase, for example potassium hydroxide.

In another embodiment the invention provides a process for preparing acompound of formula (III) wherein R₃ is methyl and R₁₀ is benzyl,comprising reacting a compound of formula (IV)

wherein R₂, R₄, R₅, W, X, Y and Z are as defined above, with a compoundof formula (IX)

wherein R₁ is as defined above, in the presence of a suitable base suchas pyridine or DIPEA. In one embodiment the reaction is carried out inthe presence of a suitable base and DMAP.

In another embodiment the invention provides a process for preparing acompound of formula (IV) wherein R₃ is methyl, comprising reacting acompound of formula (V)

with a compound of formula (VII)

wherein R₂ is as defined above; and a compound of formula (VIII)

wherein R₄, R₅, W, X, Y and Z are as defined above, in the presence of asuitable acid catalyst for example, P(OPh)₂(O)OH.

In another embodiment the invention provides a process for preparing acompound of formula (V) wherein R₃ is methyl, comprising oxidation of acompound of formula (VI)

in the presence of a phosphine ligand. In one embodiment the oxidisingagent is DIAD and the phosphine ligand is PPh₃.

In another embodiment the invention provides a process for preparing acompound of formula (XX) comprising reacting a compound of formula (X)

wherein R₁ R₂, R₃, R₄, R₅, W, X, Y and Z are as defined above, withacetic acid and sodium nitrite.

Compounds of formulae (VI), (VII), (VIII), (Villa), (VIIIb), (VIIIc),(IX), (X), (Xa), (Xb), (XI), (XIII), (XIIIa), (XIV), (XVII), (XVIIa),(XXIX), (XXX), (XXXIIa), (XXXIIb) and (XLV) are commercially availableor can be readily synthesised by known methods.

It will be appreciated by those skilled in the art that it may beadvantageous to protect one or more functional groups of the compoundsdescribed above. Examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (4th edition, J. Wiley and Sons, 2006). Suitable amineprotecting groups include acyl (e.g. acetyl, carbamate (e.g.2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl ort-butoxycarbonyl)and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric acid in dioxane or trifluoroaceticacid in dichloromethane) or reductively (e.g. hydrogenolysis of a benzylor benzyloxycarbonyl group or reductive removal of a2′,2′,2′-trichloroethoxycarbonyl group using zinc in acetic acid) asappropriate. Other suitable amine protecting groups includetrifluoroacetyl (—COCF₃) which may be removed by base catalysedhydrolysis.

It will be appreciated that in any of the routes described above, theprecise order of the synthetic steps by which the various groups andmoieties are introduced into the molecule may be varied. It will bewithin the skill of the practitioner in the art to ensure that groups ormoieties introduced at one stage of the process will not be affected bysubsequent transformations and reactions, and to select the order ofsynthetic steps accordingly.

Certain intermediate compounds described above form a yet further aspectof the invention.

The compounds of formula (I) and salts thereof are bromodomaininhibitors, and thus are believed to have potential utility in thetreatment of diseases or conditions for which a bromodomain inhibitor isindicated.

The present invention thus provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in therapy. Thecompound of formula (I) or a pharmaceutically salt thereof can be usedin the treatment of diseases or conditions for which a bromodomaininhibitor is indicated.

The present invention thus provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of anydiseases or conditions for which a bromodomain inhibitor is indicated.In one embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofacute or chronic auto-immune and/or inflammatory conditions. In anotherembodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofdiseases or conditions which involve inflammatory responses toinfections with bacteria, viruses, fungi, parasites or their toxins. Inanother embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofviral infections. In a further embodiment there is provided a compoundof formula (I) or a pharmaceutically acceptable salt thereof for use inthe treatment of cancer.

Also provided is the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of diseases or conditions for which abromodomain inhibitor is indicated. In one embodiment there is providedthe use of a compound of formula (I) or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment ofacute or chronic auto-immune and/or inflammatory conditions. In anotherembodiment there is provided the use a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for in the treatment of diseases or conditions which involveinflammatory responses to infections with bacteria, viruses, fungi,parasites or their toxins. In another embodiment there is provided theuse a compound of formula (I) or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for in the treatment of viralinfections. In another embodiment there is provided the use a compoundof formula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for in the treatment of cancer.

Also provided is a method of treating diseases or conditions for which abromodomain inhibitor is indicated in a subject in need thereof whichcomprises administering a therapeutically effective amount of compoundof formula (I) or a pharmaceutically acceptable salt thereof. In oneembodiment there is provided a method of treating acute or chronicauto-immune and/or inflammatory conditions in a subject in need thereofwhich comprises administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.In another embodiment there is provided a method of treating diseases orconditions which involve inflammatory responses to infections withbacteria, viruses, fungi, parasites or their toxins in a subject in needthereof which comprises administering a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof. In another embodiment there is provided a method of treatingviral infections in a subject in need thereof which comprisesadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof. In furtherembodiment there is provided a method of treating cancer in a subject inneed thereof which comprises administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Suitably the subject in need thereof is a mammal, particularly a human.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, or subject (e.g. a human) that is beingsought, for instance, by a researcher or clinician. Furthermore, theterm “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function.

Bromodomain inhibitors are believed to be useful in the treatment of avariety of diseases or conditions related to systemic or tissueinflammation, inflammatory responses to infection or hypoxia, cellularactivation and proliferation, lipid metabolism, fibrosis and in theprevention and treatment of viral infections.

Bromodomain inhibitors may be useful in the treatment of a wide varietyof acute or chronic autoimmune and/or inflammatory conditions such asrheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemiclupus erythematosus, multiple sclerosis, inflammatory bowel disease(Crohn's disease and Ulcerative colitis), asthma, chronic obstructiveairways disease, pneumonitis, myocarditis, pericarditis, myositis,eczema, dermatitis (including atopic dermatitis), alopecia, vitiligo,bullous skin diseases, nephritis, vasculitis, hypercholesterolemia,atherosclerosis, Alzheimer's disease, depression, Sjögren's syndrome,sialoadenitis, central retinal vein occlusion, branched retinal veinocclusion, Irvine-Gass syndrome (post cataract and post-surgical),retinitis pigmentosa, pars planitis, birdshot retinochoroidopathy,epiretinal membrane, cystic macular edema, parafoveal telengiectasis,tractional maculopathies, vitreomacular traction syndromes, retinaldetachment, neuroretinitis, idiopathic macular edema, retinitis, dry eye(keratoconjunctivitis Sicca), vernal keratoconjunctivitis, atopickeratoconjunctivitis, uveitis (such as anterior uveitis, pan uveitis,posterior uveitis, uveitis-associated macular edema), scleritis,diabetic retinopathy, diabetic macula edema, age-related maculardystrophy, hepatitis, pancreatitis, primary biliary cirrhosis,sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis,type I diabetes, giant cell arteritis, nephritis including lupusnephritis, vasculitis with organ involvement such as glomerulonephritis,vasculitis including giant cell arteritis, Wegener's granulomatosis,Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu'sArteritis, pyoderma gangrenosum, vasculitis with organ involvement andacute rejection of transplanted organs.

In one embodiment the acute or chronic autoimmune and/or inflammatorycondition is a disorder of lipid metabolism via the regulation of APO-A1such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.

In another embodiment the acute or chronic autoimmune and/orinflammatory condition is a respiratory disorder such as asthma orchronic obstructive airways disease.

In another embodiment the acute or chronic autoimmune and/orinflammatory condition is a systemic inflammatory disorder such asrheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemiclupus erythematosus, multiple sclerosis or inflammatory bowel disease(Crohn's disease and Ulcerative colitis).

In another embodiment the acute or chronic autoimmune and/orinflammatory condition is multiple sclerosis.

In a further embodiment the acute or chronic autoimmune and/orinflammatory condition is Type I diabetes.

Bromodomain inhibitors may be useful in the treatment of diseases orconditions which involve inflammatory responses to infections withbacteria, viruses, fungi, parasites or their toxins, such as sepsis,acute sepsis, sepsis syndrome, septic shock, endotoxaemia, systemicinflammatory response syndrome (SIRS), multi-organ dysfunction syndrome,toxic shock syndrome, acute lung injury, ARDS (adult respiratorydistress syndrome), acute renal failure, fulminant hepatitis, burns,acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimerreactions, encephalitis, myelitis, meningitis, malaria and SIRSassociated with viral infections such as influenza, herpes zoster,herpes simplex and coronavirus. In one embodiment the disease orcondition which involves an inflammatory response to an infection withbacteria, a virus, fungi, a parasite or their toxins is acute sepsis.

Bromodomain inhibitors may be useful in the treatment of conditionsassociated with ischaemia-reperfusion injury such as myocardialinfarction, cerebro-vascular ischaemia (stroke), acute coronarysyndromes, renal reperfusion injury, organ transplantation, coronaryartery bypass grafting, cardio-pulmonary bypass procedures, pulmonary,renal, hepatic, gastro-intestinal or peripheral limb embolism.

Bromodomain inhibitors may be useful in the treatment of fibroticconditions such as idiopathic pulmonary fibrosis, renal fibrosis,post-operative stricture, keloid scar formation, scleroderma (includingmorphea) and cardiac fibrosis.

Bromodomain inhibitors may be useful in the treatment of viralinfections such as herpes simplex infections and reactivations, coldsores, herpes zoster infections and reactivations, chickenpox, shingles,human papilloma virus (HPV), human immunodeficiency virus (HIV),cervical neoplasia, adenovirus infections, including acute respiratorydisease, poxvirus infections such as cowpox and smallpox and Africanswine fever virus. In one embodiment the viral infection is a HPVinfection of skin or cervical epithelia. In another embodiment the viralinfection is a latent HIV infection.

Bromodomain inhibitors may be useful in the treatment of cancer,including hematological (such as leukaemia, lymphoma and multiplemyeloma), epithelial including lung, breast and colon carcinomas,midline carcinomas, mesenchymal, hepatic, renal and neurologicaltumours.

Bromodomain inhibitors may be useful in the treatment of one or morecancers selected from brain cancer (gliomas), glioblastomas,Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease,breast cancer, inflammatory breast cancer, colorectal cancer, Wilm'stumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma,colon cancer, head and neck cancer, kidney cancer, lung cancer, livercancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreaticcancer, prostate cancer, sarcoma cancer, osteosarcoma, giant cell tumorof bone, thyroid cancer, lymphoblastic T-cell leukemia, chronicmyelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia,acute lymphoblastic leukemia, acute myelogenous leukemia, chronicneutrophilic leukemia, acute lymphoblastic T-cell leukemia,plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia,multiple myeloma, megakaryoblastic leukemia, acute megakaryocyticleukemia, promyelocytic leukemia, mixed lineage leukaemia,erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkinslymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicularlymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvalcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor), NUT-midline carcinoma and testicularcancer.

In one embodiment the cancer is a leukaemia, for example a leukaemiaselected from acute monocytic leukemia, acute myelogenous leukemia,chronic myelogenous leukemia, chronic lymphocytic leukemia and mixedlineage leukaemia (MLL). In another embodiment the cancer is NUT-midlinecarcinoma. In another embodiment the cancer is multiple myeloma. Inanother embodiment the cancer is a lung cancer such as small cell lungcancer (SCLC). In another embodiment the cancer is a neuroblastoma. Inanother embodiment the cancer is Burkitt's lymphoma. In anotherembodiment the cancer is cervical cancer. In another embodiment thecancer is esophageal cancer. In another embodiment the cancer is ovariancancer. In another embodiment the cancer is breast cancer. In anotherembodiment the cancer is colarectal cancer.

In one embodiment the disease or condition for which a bromodomaininhibitor is indicated is selected from diseases associated withsystemic inflammatory response syndrome, such as sepsis, burns,pancreatitis, major trauma, haemorrhage and ischaemia. In thisembodiment the bromodomain inhibitor would be administered at the pointof diagnosis to reduce the incidence of: SIRS, the onset of shock,multi-organ dysfunction syndrome, which includes the onset of acute lunginjury, ARDS, acute renal, hepatic, cardiac or gastro-intestinal injuryand mortality. In another embodiment the bromodomain inhibitor would beadministered prior to surgical or other procedures associated with ahigh risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS(multiple organ dysfunction syndrome). In a particular embodiment thedisease or condition for which a bromodomain inhibitor is indicated issepsis, sepsis syndrome, septic shock and endotoxaemia. In anotherembodiment, the bromodomain inhibitor is indicated for the treatment ofacute or chronic pancreatitis. In another embodiment the bromodomain isindicated for the treatment of burns.

As used herein the reference to the “treatment” of a particular diseaseor condition includes the prevention or prophylaxis of such a disease orcondition.

The term “diseases or conditions for which a bromodomain inhibitor isindicated”, is intended to include each of or all of the above diseasesor conditions.

The invention further provides for a method for inhibiting a bromodomainwhich comprises contacting the bromodomain with a compound of formula(I) or a pharmaceutically acceptable salt thereof.

While it is possible that for use in therapy, a compound of formula (I)as well as pharmaceutically acceptable salts thereof may be administeredas the raw chemical, it is common to present the active ingredient as apharmaceutical composition.

The present invention therefore provides in a further aspect apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt and one or more pharmaceuticallyacceptable carriers, diluents or excipients. The compounds of formula(I) and pharmaceutically acceptable salts are as described above. Thecarrier(s), diluent(s) or excipient(s) must be acceptable in the senseof being compatible with the other ingredients of the composition andnot deleterious to the recipient thereof. In accordance with anotheraspect of the invention there is also provided a process for thepreparation of a pharmaceutical composition including admixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,with one or more pharmaceutically acceptable carriers, diluents orexcipients. The pharmaceutical composition can be used in the treatmentof any of the conditions described herein.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will be readily understood that they areeach preferably provided in substantially pure form, for example, atleast 85% pure, especially at least 98% pure (% in a weight for weightbasis).

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Such unit doses may therefore be administered more than once a day.Preferred unit dosage compositions are those containing a daily dose orsub-dose (for administration more than once a day), as herein aboverecited, or an appropriate fraction thereof, of an active ingredient.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, inhaled, intranasal, topical (including buccal,sublingual or transdermal), ocular (including topical, intraocular,subconjunctival, episcleral, sub-Tenon), vaginal or parenteral(including subcutaneous, intramuscular, intravenous or intradermal)route. Such compositions may be prepared by any method known in the artof pharmacy, for example by bringing into association the activeingredient with the carrier(s) or excipient(s).

In one embodiment the pharmaceutical composition is adapted forparenteral administration, particularly intravenous administration.

In one embodiment the pharmaceutical composition is adapted for oraladministration.

In one embodiment the pharmaceutical composition is adapted for topicaladministration.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe composition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders suitable for incorporating intotablets or capsules may be prepared by reducing the compound to asuitable fine size (e.g. by micronisation) and mixing with a similarlyprepared pharmaceutical carrier such as an edible carbohydrate, forexample, starch or mannitol. Flavoring, preservative, dispersing andcoloring agent can also be present.

Capsules may be made by preparing a powder mixture, as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, glidants,lubricants, sweetening agents, flavours, disintegrating agents andcoloring agents can also be incorporated into the mixture. Suitablebinders include starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude starch, methyl cellulose, agar, bentonite, xanthan gum and thelike. Tablets are formulated, for example, by preparing a powdermixture, granulating or slugging, adding a lubricant and disintegrantand pressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of formula (I) and pharmaceutically acceptable salts thereofcan also be combined with a free flowing inert carrier and compressedinto tablets directly without going through the granulating or sluggingsteps. A clear or opaque protective coating consisting of a sealing coatof shellac, a coating of sugar or polymeric material and a polishcoating of wax can be provided. Dyestuffs can be added to these coatingsto distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Compositions for oral administration may be designed to provide amodified release profile so as to sustain or otherwise control therelease of the therapeutically active agent.

Where appropriate, dosage unit compositions for oral administration canbe microencapsulated. The composition may be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, emulsions, lotions,powders, solutions, pastes, gels, foams, sprays, aerosols or oils. Suchpharmaceutical compositions may include conventional additives whichinclude, but are not limited to, preservatives, solvents to assist drugpenetration, co-solvents, emollients, propellants, viscosity modifyingagents (gelling agents), surfactants and carriers. In one embodimentthere is provided a pharmaceutical composition adapted for topicaladministration which comprises between 0.01-10%, or between 0.01-1% ofthe compound of formula (I), or a pharmaceutically acceptable saltthereof, by weight of the composition.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions are preferably applied as a topical ointment,cream, gel, spray or foam. When formulated in an ointment, the activeingredient may be employed with either a paraffinic or a water-miscibleointment base. Alternatively, the active ingredient may be formulated ina cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.Compositions to be administered to the eye will have ophthalmicallycompatible pH and osmolality. One or more ophthalmically acceptable pHadjusting agents and/or buffering agents can be included in acomposition of the invention, including acids such as acetic, boric,citric, lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, and sodium lactate; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases, and bufferscan be included in an amount required to maintain pH of the compositionin an ophthalmically acceptable range. One or more ophthalmicallyacceptable salts can be included in the composition in an amountsufficient to bring osmolality of the composition into an ophthalmicallyacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions.

The ocular delivery device may be designed for the controlled release ofone or more therapeutic agents with multiple defined release rates andsustained dose kinetics and permeability. Controlled release may beobtained through the design of polymeric matrices incorporatingdifferent choices and properties of biodegradable/bioerodable polymers(e.g. poly(ethylene vinyl) acetate (EVA), superhydrolyzed PVA),hydroxyalkyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), polycaprolactone, poly(glycolic) acid, poly(lactic)acid, polyanhydride, of polymer molecular weights, polymercrystallinity, copolymer ratios, processing conditions, surface finish,geometry, excipient addition and polymeric coatings that will enhancedrug diffusion, erosion, dissolution and osmosis.

Pharmaceutical compositions for ocular delivery also include in situgellable aqueous composition. Such a composition comprises a gellingagent in a concentration effective to promote gelling upon contact withthe eye or with lacrimal fluid. Suitable gelling agents include but arenot limited to thermosetting polymers. The term “in situ gellable” asused herein is includes not only liquids of low viscosity that form gelsupon contact with the eye or with lacrimal fluid, but also includes moreviscous liquids such as semi-fluid and thixotropic gels that exhibitsubstantially increased viscosity or gel stiffness upon administrationto the eye. See, for example, Ludwig (2005) Adv. Drug Deliv. Rev. 3;57:1595-639, herein incorporated by reference for purposes of itsteachings of examples of polymers for use in ocular drug delivery.

Dosage forms for nasal or inhaled administration may conveniently beformulated as aerosols, solutions, suspensions, gels or dry powders.

For compositions suitable and/or adapted for inhaled administration, itis preferred that the compound of formula (I) or a pharmaceuticallyacceptable salt thereof, is in a particle-size-reduced form e.g.obtained by micronisation. The preferable particle size of thesize-reduced (e.g. micronised) compound or salt is defined by a D50value of about 0.5 to about 10 microns (for example as measured usinglaser diffraction).

Aerosol formulations, e.g. for inhaled administration, can comprise asolution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent. Aerosolformulations can be presented in single or multidose quantities insterile form in a sealed container, which can take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler) which is intended for disposalonce the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferablycontains a suitable propellant under pressure such as compressed air,carbon dioxide or an organic propellant such as a hydrofluorocarbon(HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropaneand 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also takethe form of a pump-atomiser. The pressurised aerosol may contain asolution or a suspension of the active compound. This may require theincorporation of additional excipients e.g. co-solvents and/orsurfactants to improve the dispersion characteristics and homogeneity ofsuspension formulations. Solution formulations may also require theaddition of co-solvents such as ethanol.

For pharmaceutical compositions suitable and/or adapted for inhaledadministration, the pharmaceutical composition may be a dry powderinhalable composition. Such a composition can comprise a powder basesuch as lactose, glucose, trehalose, mannitol or starch, the compound offormula (I) or a pharmaceutically acceptable salt thereof (preferably inparticle-size-reduced form, e.g. in micronised form), and optionally aperformance modifier such as L-leucine or another amino acid and/ormetal salt of stearic acid such as magnesium or calcium stearate.Preferably, the dry powder inhalable composition comprises a dry powderblend of lactose e.g. lactose monohydrate and the compound of formula(I) or salt thereof. Such compositions can be administered to thepatient using a suitable device such as the DISKUS® device, marketed byGlaxoSmithKline which is for example described in GB 2242134 A.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be formulated as a fluid formulation for delivery from afluid dispenser, for example a fluid dispenser having a dispensingnozzle or dispensing orifice through which a metered dose of the fluidformulation is dispensed upon the application of a user-applied force toa pump mechanism of the fluid dispenser. Such fluid dispensers aregenerally provided with a reservoir of multiple metered doses of thefluid formulation, the doses being dispensable upon sequential pumpactuations. The dispensing nozzle or orifice may be configured forinsertion into the nostrils of the user for spray dispensing of thefluid formulation into the nasal cavity. A fluid dispenser of theaforementioned type is described and illustrated in WO-A-2005/044354.

A therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, will depend upon a number offactors including, for example, the age and weight of the subject, theprecise condition requiring treatment and its severity, the nature ofthe formulation, and the route of administration, and will ultimately beat the discretion of the attendant physician or veterinarian. In thepharmaceutical composition, each dosage unit for oral or parenteraladministration preferably contains from 0.01 to 3000 mg, more preferably0.5 to 1000 mg, of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, calculated as the free base. Each dosage unitfor nasal or inhaled administration preferably contains from 0.001 to 50mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or apharmaceutically acceptable salt thereof, calculated as the free base.

The pharmaceutically acceptable compounds of formula (I) andpharmaceutically acceptable salts thereof, can be administered in adaily dose (for an adult patient) of, for example, an oral or parenteraldose of 0.01 mg to 3000 mg per day, 0.5 to 1000 mg per day or 100 mg to2500 mg per day, or a nasal or inhaled dose of 0.001 to 50 mg per day or0.01 to 5 mg per day, of the compound of the formula (I) or apharmaceutically acceptable salt thereof, calculated as the free base.This amount may be given in a single dose per day or more usually in anumber (such as two, three, four, five or six) of sub-doses per day suchthat the total daily dose is the same. An effective amount of a saltthereof, may be determined as a proportion of the effective amount ofthe compound of formula (I) per se.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be employed alone or in combination with other therapeuticagents. Combination therapies according to the present invention thuscomprise the administration of at least one compound of formula (I) or apharmaceutically acceptable salt thereof, and the use of at least oneother therapeutically active agent. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of formula (I) or a pharmaceutically acceptable saltthereof, and at least one other therapeutically active agent. Thecompound(s) of formula (I) and pharmaceutically acceptable saltsthereof, and the other therapeutically active agent(s) may beadministered together in a single pharmaceutical composition orseparately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and pharmaceutically acceptable saltsthereof, and the other therapeutically active agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect. Thus in a further aspect, there isprovided a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof, together with one or moreother therapeutically active agents.

Thus in one aspect, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and pharmaceutical compositions comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof,according to the invention may be used in combination with or includeone or more other therapeutic agents, for example selected fromantibiotics, anti-virals, glucocorticosteroids, muscarinic antagonistsbeta-2 agonists and Vitamin D3 analogues. In a further embodiment acompound of formula (I) or a pharmaceutically acceptable salt thereofmay be used in combination with a further therapeutic agent which issuitable for the treatment of cancer. Examples of such furthertherapeutic agents are described in Cancer Principles and Practice ofOncology by V. T. Devita and S. Hellman (editors), 6^(th) edition(2001), Lippincott Williams & Wilkins Publishers. A person of ordinaryskill in the art would be able to discern which combinations of agentswould be useful based on the particular characteristics of the drugs andthe cancer involved. Further therapeutic agents to be used incombination with the compound of formula (I) or a pharmaceuticallyacceptable salt thereof include, but are not limited to,anti-microtubule agents (such as diterpenoids and vinca alkaloids);platinum coordination complexes; alkylating agents (such as nitrogenmustards, oxazaphosphorines, alkylsulphonates, nitrosoureas, andtriazenes); antibiotic agents (such as anthracyclins, actinomycins andbleomycins); topoisomerase II inhibitors (such as epipodophyllotoxins);antimetabolites (such as purine and pyrimidine analogues and anti-folatecompounds); topoisomerase I inhibitors (such as camptothecins; hormonesand hormonal analogues); signal transduction pathway inhibitors (such astyropsine receptor inhibitors); non-receptor tyrosine kinaseangiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents;epigenetic or transcriptional modulators (such as histone deacetylaseinhibitors) and cell cycle signaling inhibitors.

It will be appreciated that when the compound of formula (I) or apharmaceutically acceptable salt thereof, is administered in combinationwith other therapeutic agents normally administered by the inhaled,intravenous, oral or intranasal route, that the resultant pharmaceuticalcomposition may be administered by the same routes. Alternatively theindividual components of the composition may be administered bydifferent routes.

One embodiment of the invention encompasses combinations comprising oneor two other therapeutic agents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates, to optimise the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, thetherapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof, may be prepared by the methods described below or by similarmethods. Thus the following Intermediates and Examples serve toillustrate the preparation of the compounds of formula (I) andpharmaceutically acceptable salts thereof, and are not to be consideredas limiting the scope of the invention in any way.

General Experimental Details

All temperatures referred to are in ° C.

The names of the following compounds have been obtained using thecompound naming programme “ACD Name Pro 6.02” or ChemDraw Ultra 12.0.

Abbreviations

-   1,2-DCE 1,2-dichloroethane-   AcOH acetic acid-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   BBr₃ boron tribromide-   BOC tert-butyloxycarbonyl-   BrettPhos    2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl-   BuLi butyllithium-   CaCO₃ calcium carbonate-   Comin's reagent    N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)    methanesulfonamide-   Cs₂CO₃ cesium carbonate-   CHCl₃ chloroform-   CV column volume-   DavePhos 2-dicyclohexylphosphino-2′-(dimethylamino)biphenyl-   D6-DMSO deuterated dimethylsulfoxide-   DCM dichloromethane-   DIAD diisopropyl azodicarboxylate-   DIPEA diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   DPPA diphenylphosphoryl azide-   Et₃N triethylamine-   EtOAc ethyl acetate-   FMOC fluorenylmethyloxycarbonyl-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HCl hydrochloric acid-   HCO₂H formic acid-   IPA isopropyl alcohol-   i-PrOAc isopropylacetate-   i-Pr₂O diisopropyl ether-   K₂CO₃ potassium carbonate-   KOH potassium hydroxide-   LCMS liquid chromatography-mass spectrometry-   LiOH lithium hydroxide-   M molar (concentration)-   mCPBA meta-chloroperoxybenzoic acid-   MDAP mass directed autoprep-   MeCN acetonitrile-   Mel methyl iodide-   MeOH methanol-   min minute(s)-   N normal (concentration)-   N₂ nitrogen-   Na₂CO₃ sodium carbonate-   NaI sodium iodide-   NaH sodium hydride-   NaNO₂ sodium nitrite-   Na(OAc)₃BH sodium triacetoxy borohydride-   NaO^(t)Bu sodium tert-butoxide-   Na₂SO₄ sodium sulphate-   NBS N-bromosuccinimide-   NEt₃ triethylamine-   NMP N-methyl-2-pyrrolidone-   OTf trifluoromethanesulfonate-   PEPPSI pyridine-enhanced precatalyst preparation stabilization and    initiation-   Pd/C palladium on carbon-   PdCl₂(PPh)₃ bis(triphenylphosphine)palladium(II) dichloride-   PdCl₂(dppf) [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)    dichloride-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (0)-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   P(OPh)₂(O)OH diphenyl hydrogen phosphate-   PPh₃ triphenylphosphine-   Rh cat. rhodium catalyst-   Rt retention time-   rt room temperature-   SPE solid phase extraction-   TBAF tetra-n-butylammonium fluoride-   TBME tert-butyl methyl ether-   Tf₂O trifluoromethanesulfonic anhydride-   TFA trifluoroacetic acid-   TPPTS 3,3′,3″-phosphinidynetris(benzenesulfonic acid) trisodium salt-   TMSCl trimethylsilyl chloride-   THE tetrahydrofuran-   UPLC ultra performance liquid chromatography-   XantPhos    1,1′-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[1,1-diphenylphosphine-   X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl-   Yb(OTf)₃ ytterbium triflate

LCMS Methodology

Formic Method

LC Conditions

The UPLC analysis was conducted on an Acquity UPLC BEH C18 column (50mm×2.1 mm, i.d. 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=0.1% v/v solution of formic acid in waterB=0.1% v/v solution of formic acid in acetonitrile

The gradient employed was:

Time (min) Flow rate (mL/min) % A % B 0 1 97 3 1.5 1 0 100 1.9 1 0 1002.0 1 97 3

The detection was a summed signal from wavelength of 210 nm to 350 nm.

MS Conditions

MS: Waters ZQ

Ionisation mode: Alternate-scan positive and negative electrospray

Scan range: 100 to 1000 AMU

Scan time 0.27 sec

Inter scan delay 0.10 sec

HpH Method

LC Conditions

The UPLC analysis was conducted on an Acquity UPLC BEH C18 column (50mm×2.1 mm, i.d. 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=10 mM ammonium hydrogen carbonate in water adjusted to pH10 withammonia solutionB=acetonitrile

The gradient employed was:

Time (min) Flow rate (ml/min) % A % B 0 1 99 1 1.5 1 3 97 1.9 1 3 97 2.01 0 100

The UV detection was a summed signal from wavelength of 210 nm to 350nm.

MS Conditions

MS: Waters ZQ

Ionisation mode: Alternate-scan positive and negative electrospray

Scan range: 100 to 1000 AMU

Scan time: 0.27 sec

Inter scan delay: 0.10 sec

NMR

Spectra were run on a 400 mHz NMR machine at either 302 K or for VTspectra at 392-393 K.

Intermediate 1: (E)-benzyl prop-1-en-1-ylcarbamate

Diisopropyl azodicarboxylate (4.05 mL, 20.85 mmol) was added drop-wiseover 5 min to a solution of triphenylphosphine (5.47 g, 20.85 mmol) inTHE (125 mL) at −78° C. The mixture was stirred for 15 min and then(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoic acid (4.8 g,18.95 mmol) in THE (50 mL) was added drop-wise over 10 min still at −78°C. The solution was stirred for 1 h at −78° C. and allowed to warm to rtand stirred overnight. The solvent was then evaporated in vacuo and theresidue was loaded onto a 100 g silica cartridge and purified by columnchromatography using a gradient 0-30% of ethyl acetate in cyclohexane.Desired fractions were combined and evaporated in vacuo to afford theproduct as a white solid (3.06 g).

LCMS (2 min Formic): Rt=0.99 min, [MH]⁺ not observed.

Intermediate 2: rac-benzyl((2S,3S,4R)-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Under a nitrogen atmosphere, to a solution of acetaldehyde (0.027 mL,0.475 mmol) in dry DCM (3 mL) was added 4-bromoaniline (82 mg, 0.475mmol). The reaction was stirred at rt for 1 h and then cooled to 0° C.Solutions of diphenyl hydrogen phosphate (12 mg, 0.048 mmol) in dry DCM(1.5 mL) and (E)-benzyl prop-1-en-1-ylcarbamate (for a preparation seeIntermediate 1, 100 mg, 0.523 mmol) in dry DCM (1.5 mL) were added. Thereaction was stirred at 0° C. for 2 h and allowed to stand at rtovernight. The solvent was then evaporated in vacuo. The residue wasloaded onto a 25 g silica cartridge and purified by columnchromatography using a gradient 0-30% of ethyl acetate in cyclohexane.Desired fractions were combined and evaporated in vacuo to afford theproduct as a white solid (129 mg). LCMS (2 min Formic): Rt=1.23 min,[MH]⁺=389, 391.

Intermediate 3: rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

rac-Benzyl((2S,3S,4R)-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 2, 284 mg, 0.728 mmol) was taken upin dry dichloromethane (DCM) (5 mL) under nitrogen at rt. Pyridine(0.177 mL, 2.185 mmol) then acetyl chloride (0.078 mL, 1.092 mmol) wereadded and the reaction was stirred for 2 h. The reaction was partitionedbetween ethyl acetate (40 mL) and saturated sodium bicarbonate (20 mL).The organic layer was extracted and washed with water (30 mL) and brine(30 mL) and then dried through a hydrophobic frit and concentrated invacuo. The crude product was taken up in the minimum of DCM and appliedto a 100 g silica cartridge and eluted with a gradient 0-100% of ethylacetate in cyclohexane. Desired fractions were combined and evaporatedin vacuo to afford the product as a white solid (286 mg).

LCMS (2 min Formic): Rt=1.13 min, [MH]⁺=431, 433.

Intermediate 4: rac-benzyl((2S,3S,4R)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Under a nitrogen atmosphere, to a solution of acetaldehyde (1.35 mL,24.0 mmol) in dry DCM (130 mL) was added aniline (2.19 mL, 24 mmol). Thereaction was stirred at rt for 1 h and then cooled to 0° C. Solutions ofdiphenyl hydrogen phosphate (0.60 g, 2.40 mmol) in dry DCM (60 mL) and(E)-benzyl prop-1-en-1-ylcarbamate (for a preparation see Intermediate1, 5.05 g, 26.4 mmol) in dry DCM (60 mL) were added. The reaction wasstirred at 0° C. for 3 h and at rt for 1 h. Acetaldehyde (1.347 mL, 24.0mmol) was then added and the reaction mixture was stirred at rtovernight. Acetaldehyde (1 mL) was then added and the reaction mixturewas stirred at rt for 1 h. Acetaldehyde (1 mL) was then added and thereaction mixture was stirred at rt for 1 h. The solvent was thenevaporated in vacuo, the residue was loaded onto two 100 g silicacartridges and purified by column chromatography using a gradient 0-30%of ethyl acetate in cyclohexane. Desired fractions from bothpurifications were combined and evaporated in vacuo to afford theproduct as a white solid (3.65 g).

LCMS (2 min Formic): Rt=1.08 min, [MH]⁺=311.

Intermediate 5: rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of rac-benzyl((2S,3S,4R)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (fora preparation see Intermediate 4, 3.22 g, 10.37 mmol) in anhydrousdichloromethane (DCM) (75 mL) was treated with pyridine (2.51 mL, 31.1mmol) and acetyl chloride (1.11 mL, 15.56 mmol). The solution wasstirred at rt under nitrogen for 1 h. The reaction mixture wastransferred to a separating funnel then washed with 2M aq. HCl (50 mL)followed by sat. aqueous sodium bicarbonate (50 mL) and water (50 mL).The organic layer was dried through a hydrophobic frit and the solventwas removed by rotary evaporation to give the product as a beige solid(3.61 g, 10.24 mmol, 99% yield). LCMS (2 min Formic): Rt=1.01 min,[MH]⁺=353.

Intermediate 6:rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 5, 3.55 g, 10.07 mmol) was dissolvedin methanol (100 mL) and was then passed through a 10% Pd/C cartridge ona H-cube (rt, full H₂ mode) to give a colourless filtrate. This filtratewas concentrated in vacuo to afford the product as a colourless oilwhich crystallised over time to become a beige solid (2.27 g). LCMS (2min Formic): Rt=0.38 min, [MH]⁺=219.

Intermediate 7: rac-tert-butyl4-(3-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)piperazine-1-carboxylate

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 100 mg, 0.458 mmol), tert-butyl4-(3-bromophenyl)piperazine-1-carboxylate (0.127 mL, 0.550 mmol),tris(dibenzylideneacetone)dipalladium(0) (20.97 mg, 0.023 mmol),DavePhos (18.03 mg, 0.046 mmol), sodium tert-butoxide (66.0 mg, 0.687mmol) and 1,4-dioxane (4 mL). The reaction mixture was then heated andstirred at 100° C. in a greenhouse reactor for 1 h. After cooling to rt,the reaction mixture was filtered through a pad of celite (rinsed withEtOAc). The filtrate was then evaporated in vacuo. The residue waspurified by MDAP (Formic). The desired fractions were combined andevaporated in vacuo to afford the product as a white solid (183.6 mg).

LCMS (2 min formic): Rt=1.23 min, [MH]⁺=479.

Intermediate 8: rac-benzyl((2S,3R,4R)-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Under an atmosphere of nitrogen, to a solution of 4-bromoaniline (5 g,29.1 mmol) in dry dichloromethane (DCM) (80 mL) was addedpropionaldehyde (2.31 mL, 32.0 mmol). The mixture was stirred at rt for1.5 h then cooled to 0° C. To the solution was added diphenyl hydrogenphosphate (0.727 g, 2.91 mmol) in dry dichloromethane (DCM) (30 mL)followed by (E)-benzyl prop-1-en-1-ylcarbamate (for a preparation seeIntermediate 1, 6.1 g, 31.9 mmol) in dry dichloromethane (DCM) (30 mL).The solution was stirred at 0° C. for 1 h then allowed to warm to rtwith stirring over the weekend. The reaction mixture was washed withsat. aq. NaHCO₃ (100 mL) and the aqueous layer was extracted with DCM(100 mL). The combined organics were dried through a hydrophobic fritand the solvent was removed by rotary evaporation to leave the crude.Purification was undertaken by flash column chromatography. The crudematerial was loaded onto a 340 g silica column and eluted using agraduating solvent system of 0-30% ethyl acetate in cyclohexane.Combination and evaporation of the desired fractions gave the product asan off-white solid (10 g).

LCMS (2 min Formic): Rt=1.29 min, [MH]⁺=403, 405.

Intermediate 9: rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of rac-benzyl((2S,3S,4R)-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 8, 1.21 g, 3.0 mmol) in anhydrousdichloromethane (DCM) (30 mL) was added pyridine (0.726 mL, 9.0 mmol)followed by acetyl chloride (0.321 mL, 4.50 mmol). The reaction mixturewas stirred at rt under nitrogen for 1 h. Saturated sodium bicarbonate(50 mL) was added and the reaction mixture partitioned. The aqueouslayer was extracted with DCM (2×50 mL). The organic layers werecombined, dried and evaporated in vacuo. The solid was dissolved in DCMand loaded onto a 100 g silica cartridge and purified using a gradientof 0-50% ethyl acetate in cyclohexane. The required fractions werecombined and evaporated in vacuo and dried in the vacuum oven to givethe required product as a pale yellow/white solid (1.15 g, 2.59 mmol,86%). LCMS (2 min Formic): Rt=1.17 min, [MH]⁺=445, 447.

Intermediate 10:rac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonehydrobromide

rac-Benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 9, 550 mg, 1.235 mmol) was taken upin ethanol (10 mL) and treated with 10% Pd/C (50 mg, 0.235 mmol) andallowed to stir under an atmosphere of hydrogen for 4 h. The catalystwas removed by filtering through celite and washing with more EtOH, thefiltrate was concentrated and dried to give the product as a buff solid(369 mg).

LCMS (2 min Formic): Rt=0.47 min, [MH]⁺=216 (loss of NH₂ ⁻).

Intermediate 11rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The 2-bromo-6-methylpyridine (0.36 mL, 3.10 mmol),rac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonehydrobromide (for a preparation see Intermediate 10, 360 mg, 1.55 mmol),DavePhos (45.2 mg, 0.115 mmol), Pd₂(dba)₃ (63.1 mg, 0.069 mmol), sodiumtert-butoxide (155 mg, 1.609 mmol) and 1,4-dioxane (10 mL) were placedin a round bottomed flask and allowed to stir at 100° C. for 4 h. Thereaction was allowed to stir at 100° C. for a further 18 h and then wastreated with more Pd₂(dba)₃ (63.1 mg, 0.069 mmol) and DavePhos (45.2 mg,0.115 mmol) and allowed to stir at 100° C. for 24 h. The reaction waspartitioned between water and EtOAc. The organic layer was washed withbrine, dried using a hydrophobic frit and concentrated to a brown solid.This solid was purified using a 25 g silica column eluting with agradient 0-50% EtOAc:cyclohexane. One major peak was eluted but with ashoulder, the non-shoulder fractions were combined and concentrated togive the product as a light brown solid (167 mg). LCMS (2 min Formic):Rt=0.66 min, [MH]⁺=324.

Intermediate 12: rac-benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Under an atmosphere of nitrogen, to a solution of 4-bromoaniline (4.03g, 23.43 mmol) in dry dichloromethane (DCM) (60 mL) was addedcyclopropanecarbaldehyde (1.75 mL, 23.42 mmol). The mixture was stirredat rt for 1.5 h then cooled to 0° C. To the solution was added diphenylhydrogen phosphate (0.586 g, 2.343 mmol) in dry dichloromethane (DCM)(30 mL) followed by (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 4.9 g, 25.6 mmol) in dry dichloromethane(DCM) (30 mL). The solution was stirred at 0° C. for 1 h then allowed towarm to rt with stirring over the weekend. The reaction mixture waswashed with 2M aq. NaOH (60 mL) followed by water (60 mL). The organiclayer was dried through a hydrophobic frit and the solvent was removedby rotary evaporation. The residue was loaded in CHCl₃ (25 mL) andpurified on a 330 g silica cartridge using a gradient of 0-40% EtOAc incyclohexane. The appropriate fractions were combined and the solvent wasremoved by rotary evaporation to give the product as an off-white solid(8.17 g, 19.67 mmol, 84%). LCMS (2 min Formic): Rt=1.30 min, [MH]⁺=415,417.

Intermediate 13: rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

rac-Benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 12, 8.17 g, 19.67 mmol) and pyridine(4.77 mL, 59.0 mmol) in anhydrous dichloromethane (DCM) (120 mL) wastreated with acetyl chloride (2.1 mL, 29.5 mmol). The mixture wasstirred at rt under an atmosphere of nitrogen for 1.5 h. The reactionmixture was transferred to a separating funnel then washed with 2M aq.HCl (50 mL) followed by sat. aq. NaHCO₃ (50 mL) and water (50 mL). Theorganic layer was dried through a hydrophobic frit and the solvent wasremoved by rotary evaporation to give the product as an off-white solid(9.03 g, 19.74 mmol, 100%). LCMS (2 min Formic): Rt=1.18 min, [MH]⁺=457,459.

Intermediate 14:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-Benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 13, 2.51 g, 5.49 mmol), 10% Pd/C(400 mg, 3.76 mmol) and ammonium formate (3.46 g, 54.9 mmol) were alladded to a flask under nitrogen. To this was added ethanol (50 mL) andethyl acetate (15 mL), forming a suspension of both the startingmaterial and the catalyst. The suspension was stirred at reflux for ˜1h. The reaction mixture was washed through a 10 g celite cartridge withethanol, followed by ethyl acetate, and the mixture collected. Thefiltered solvent was evaporated in vacuo to afford a white powdery solid(1.79 g). The solid was dissolved in methanol loaded onto a 50 g SCX-2SPE cartridge, washed with 4 CVs MeOH, and the product eluted with 4 CVsof 2M methanolic ammonia. The appropriate fractions were collected andevaporated in vacuo to afford a clear, pale yellow oil. The oil was heldunder high vacuum overnight, to afford a white crystalline solid (1.2003g, 4.91 mmol, 90%).

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=245.

Intermediate 15: Cyclobutanecarbaldehyde

To a solution of cyclobutylmethanol (1.0 g, 11.61 mmol) in anhydrous DCM(10 mL) was added a solution of 24% KBr in water (0.63 mL, 11.61 mmol).To this mixture was added a solution of sat. NaHCO₃ (aq) (1.5 mL, 11.61mmol) and the mixture cooled to 0° C. To this was added TEMPO (18 mg,0.115 mmol) and the mixture stirred for 20 min. Slowly ˜5% sodiumhypochlorite solution (1.9 mL, 30.8 mmol) was charged to the mixture andstirred for 30 min. Then a solution of 8.25% KH₂PO₄ in water (4.0 mL,11.61 mmol) was added and the mixture stirred for an additional 30 minwhile warming to rt. The layers were allowed to separate and the organiclayer dried through a hydrophobic frit and then over MgSO₄. The organiclayer was split into 2x˜5 mL portions. One portion was carefullyevaporated under vacuum in an ice/water bath to remove most of thesolvent. The resulting yellow gum (˜0.5 g) which contained the startingalcohol is the major component with 10% desired aldehyde present. Thesecond separated 5 mL DCM solution was added to the gum to give asolution containing the product. LCMS no peak/mass ion observed.

Intermediate 16: rac-benzyl((2S,3S,4R)-2-cyclobutyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of cyclobutanecarbaldehyde (for a preparation seeIntermediate 15, 100 mg, 1.19 mmol) in anhydrous DCM (5 mL)* undernitrogen was added aniline (100 μL, 1.095 mmol). The mixture was stirredat rt for 1.5 h then cooled to 0° C. To the solution was added diphenylhydrogen phosphate (27 mg, 0.110 mmol) in anhydrous DCM (2.0 mL)followed by (E)-benzyl prop-1-en-1-ylcarbamate (209 mg, 1.095 mmol) inanhydrous DCM (1.0 mL). The mixture was stirred at 0° C. under nitrogenfor 1 h, then allowed to warm to rt over 20 h. The reaction mixture waswashed with sat. NaHCO₃ (aq) (10 mL) followed by water (10 mL). Theorganic layer was dried through a hydrophobic frit and the solventremoved under vacuum. The gum was loaded in CHCl₃ (5 mL) and purified bycolumn chromatography on a 100 g silica cartridge using a gradient of0-40% EtOAc in cyclohexane. The appropriate fractions were combined andthe solvent removed by rotary evaporation to give the product as a whitesolid (264 mg, 0.753 mmol, 69%). *crude mixture ofcyclobutanecarbaldehyde (˜10%) and cyclobutylmethanol in DCM (5 mL). Themass of cyclobutanecarbaldehyde in the grid was estimated from NMR ofN24241-62-100 contained in the crude mixture.

LCMS (2 min Formic): Rt=1.28 min, [MH]⁺=351.

Intermediate 17: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclobutyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-2-cyclobutyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 16, 259 mg, 0.739 mmol) in DCM (3mL) and pyridine (0.179 mL, 2.217 mmol) under nitrogen at 0° C. wasadded acetyl chloride (0.079 mL, 1.11 mmol). The mixture was stirred for15 min at 0° C. then allowed to warm to rt over 2 h. The reactionmixture was diluted with DCM (5 mL) and washed sequentially with 0.5Maqueous HCl solution (10 mL), saturated aqueous NaHCO₃ solution (10 mL)and water (10 mL). The organic layer was separated and dried through ahydrophobic frit. The solvent was removed under reduced pressure and thesolid loaded in CHCl₃ (3 mL) and purified by column chromatography on a50 g silica cartridge using a gradient of 0-10% MeOH in DCM. Theappropriate fractions were combined and the solvent removed by rotaryevaporation to give the product as a white solid (253 mg, 0.645 mmol,87%). LCMS (2 min Formic): Rt=1.15 min, [MH]⁺=393.

Intermediate 18:rac-1-((2S,3R,4R)-4-amino-2-cyclobutyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclobutyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 17, 248 mg, 0.632 mmol) in methanol(12 mL) was hydrogenated using the H-cube (rt, full H₂ mode, 1 mL/minflow rate) and a 10% Pd/C CatCart 30 as the catalyst. The eluent wasevaporated under vacuum to give the product as a colourless oil (159 mg,0.615 mmol, 97%). LCMS (2 min Formic): Rt=0.55 min, [M]⁺=228 (loss ofNH₂ ⁻).

Intermediate 19: rac-benzyl((2S,3S,4R)-2-isopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of isobutyraldehyde (0.147 mL, 1.611 mmol) in anhydrousDCM (3.0 mL) under nitrogen was added aniline (0.147 mL, 1.611 mmol).The mixture was stirred at rt for 30 min then cooled to −45° C.(acetonitrile/dry-ice bath). To the solution was added diphenyl hydrogenphosphate (40 mg, 0.160 mmol) in anhydrous DCM (0.5 mL) followed by(E)-benzyl prop-1-en-1-ylcarbamate (for a preparation see Intermediate1, 308 mg, 1.61 mmol) in anhydrous DCM (0.5 mL). The mixture was stirredat −45° C. under nitrogen for 1 h, then allowed to warm to rt over 20 h.The suspension was filtered. The solid was dried in a vacuum oven togive the product as an off-white solid (286 mg, 0.845 mmol, 53%). LCMS(2 min Formic): Rt=1.27 min, [MH]⁺=339.

Intermediate 20: rac-benzyl((2S,3R,4R)-1-acetyl-2-isopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-2-isopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(fora preparation see Intermediate 19, 274 mg, 0.81 mmol) in DCM (3.0mL) and pyridine (0.20 mL, 2.473 mmol) was added acetyl chloride (0.09mL, 1.261 mmol) and the mixture stirred for 45 min. The reaction mixturewas diluted with DCM (2 mL) and washed sequentially with 0.5M aqueousHCl solution (5 mL), saturated aqueous NaHCO₃ solution (5 mL) and water(5 mL). The organic layer was separated and dried through a hydrophobicfrit. The solvent was removed under reduced pressure and the residueloaded in DCM (3 mL) and purified by column chromatography on a 25 gsilica cartridge using a gradient of 0-15% MeOH in DCM. The appropriatefractions were combined and the solvent removed by rotary evaporation.The gum was purified by MDAP (Formic). The appropriate fractions werecombined and the solvent removed by rotary evaporation to give theproduct as a white crystals (120 mg, 0.413 mmol, 47%).

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=381.

Intermediate 21:rac-1-((2S,3R,4R)-4-amino-2-isopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-isopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 20, 195 mg, 0.513 mmol) in methanol(10 mL) was hydrogenated using the H-cube (rt, full H₂ mode, 1 mL/minflow rate) and a 10% Pd/C CatCart 30 as the catalyst. The eluent wasevaporated in vacuo to give the product as a yellow oil (125 mg, 0.507mmol, 99%). LCMS (2 min Formic): Rt=0.50 min, [MH]⁺=247.

Intermediate 22: rac-benzyl((2S,3S,4R)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of 3,3,3-trifluoropropanal (360 mg, 3.21 mmol) inanhydrous DCM (5.0 mL) under nitrogen was added aniline (0.29 mL, 3.22mmol). The mixture was stirred at rt for 1.5 h then cooled to 0° C. Tothe solution was added diphenyl hydrogen phosphate (81 mg, 0.322 mmol)in anhydrous DCM (2.0 mL) followed by (E)-benzyl prop-1-en-1-ylcarbamate(for a preparation see Intermediate 1, 615 mg, 3.22 mmol) in anhydrousDCM (1.0 mL). The mixture was stirred at 0° C. under nitrogen for 1 h,then allowed to warm to rt over 20 h. The reaction mixture was dilutedwith DCM (12 mL) and washed with sat. NaHCO₃ (aq) (20 mL) followed bywater (20 mL). The organic layer was dried through a hydrophobic fritand the solvent removed under vacuum. The resulting gum was loaded inCHCl₃ (5 mL) on to 100 g silica cartridge and purified by columnchromatography using a gradient of 0-30% EtOAc in cyclohexane. Desiredfractions were combined and the solvent removed by rotary evaporation togive the product (400 mg). LCMS (2 min Formic): Rt=1.22 min, [MH]⁺=379.

Intermediate 23: rac-benzyl((2S,3R,4R)-1-acetyl-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 22, 330 mg, 0.872 mmol) in DCM (3mL) and pyridine (0.21 mL, 2.62 mmol) under nitrogen at 0° C. was addedacetyl chloride (0.093 mL, 1.308 mmol). The mixture was stirred for 15min at 0° C. then allowed to warm to rt over 2 h. The reaction mixturewas diluted with DCM (7 mL) washed sequentially with 0.5M aqueous HClsolution (15 mL), saturated aqueous NaHCO₃ solution (15 mL) and water(15 mL). The organic layer was separated and dried through a hydrophobicfrit. The solvent was removed under reduced pressure and the solidpurified by MDAP (Formic). The appropriate fractions were combined andthe solvent removed by rotary evaporation to give the product as anoff-white solid (143 mg, 0.340 mmol, 39%). LCMS (2 min Formic): Rt=1.10min, [MH]⁺=421.

Intermediate 24:rac-1-((2S,3R,4R)-4-amino-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 23, 135 mg, 0.321 mmol) in methanol(6 mL) was hydrogenated using the H-cube (rt, full H₂ mode, 1 mL/minflow rate) and a 10% Pd/C CatCart 30 as the catalyst. The eluent wasevaporated under vacuum to give the product as a colourless oil (92 mg,0.321 mmol, 100%).

LCMS (2 min Formic): Rt=0.79 min, [MH]⁺=270 (loss of NH2⁻).

Intermediate 25: rac-benzyl((2R,3R,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (382 mg,2.191 mmol) in anhydrous DCM (3 mL) was added aniline (0.2 mL, 2.191mmol). The mixture was stirred under nitrogen at rt for 30 min thencooled to 0° C. To the solution was added diphenyl hydrogen phosphate(60 mg, 0.240 mmol) in anhydrous DCM (0.5 mL) followed by (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 419 mg,2.191 mmol) in anhydrous DCM (0.5 mL). The mixture was stirred at 0° C.under nitrogen for 1 h, then allowed to warm to rt over 21 h. Thereaction mixture was diluted with DCM (6 mL), washed with a saturatedaqueous solution of NaHCO₃ (10 mL) followed by water (10 mL). Theorganic layer was dried through a hydrophobic frit and evaporated invacuo. The residue in DCM (5 mL) was applied to a 100 g silica cartridgeand purified using a gradient of 0-100% DCM in cyclohexane. Theappropriate fractions were combined and the solvent removed by rotaryevaporation to give the product as a white solid (571 mg, 1.30 mmol,59%).

LCMS (2 min Formic): Rt=1.53 min, [MH]⁺=441.

Intermediate 26: rac-benzyl((2R,3R,4R)-1-acetyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2R,3R,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 25, 565 mg, 1.28 mmol) in DCM (8 mL)and pyridine (0.311 mL, 3.85 mmol) under nitrogen at 0° C. was addedacetyl chloride (0.137 mL, 1.923 mmol). The mixture was stirred for 15min at 0° C. then allowed to warm to rt over 2 h. The reaction mixturewas diluted with DCM (7 mL) washed sequentially with 0.5M aqueous HClsolution (15 mL), saturated aqueous NaHCO₃ solution (15 mL) and water(15 mL). The organic layer was separated and dried through a hydrophobicfrit. The solvent was removed under reduced pressure and the residueloaded in CHCl₃ (7 mL) and purified on a 100 g silica cartridge using agradient of 0-75% EtOAc in cyclohexane. The appropriate fractions werecombined and the solvent removed by rotary evaporation to give theproduct as a white solid (457 mg, 0.947 mmol, 74%).

LCMS (2 min Formic): Rt=1.40 min, [MH]⁺=483.

Intermediate 27:rac-1-((2R,3R,4R)-4-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2R,3R,4R)-1-acetyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation se Intermediate 26, 450 mg, 0.932 mmol) in methanol(19 mL) was hydrogenated using the H-cube (rt, full H₂ mode, 1 mL/minflow rate) and a 10% Pd/C CatCart 30 as the catalyst. The eluent wasevaporated under vacuum to give the product as a colourless oil (320 mg,0.918 mmol, 98%).

LCMS (2 min Formic): Rt=1.23 min, [MH]⁺=332 (loss of NH₂ ⁻).

Intermediate 28:rac-1-((2R,3R,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 0.5-2 mL microwave vessel was charged with a magnetic stirrer bar,sodium tert-butoxide (130 mg, 1.356 mmol), Pd₂(dba)₃ (41.4 mg, 0.045mmol), DavePhos (36 mg, 0.090 mmol),rac-1-((2R,3R,4R)-4-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 27, 315 mg, 0.904 mmol),bromobenzene (0.095 mL, 0.904 mmol) and anhydrous 1,4-dioxane (4.5 mL).The vessel was sealed and nitrogen was bubbled through the reactionmixture for 5 min. The reaction was heated in a microwave reactor at120° C. for 30 min. The reaction mixture was filtered through celite andwashed with EtOAc (10 mL) and the filtrate evaporated under vacuum. Theresidue was loaded in CHCl₃ (5 mL) and purified on a 100 g silicacartridge using a gradient of 0-75% EtOAc in cyclohexane. Theappropriate fractions were combined and the solvent removed by rotaryevaporation to give the product as a colourless gum (165 mg, 0.389 mmol,43%). LCMS (2 min Formic): Rt=1.48 min, [MH]⁺=425.

Intermediate 29:rac-1-((2R,3R,4R)-2-(hydroxymethyl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2R,3R,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 28, 151 mg, 0.356 mmol) in anhydrousTHE (3 mL) was added TBAF (1M solution in THF) (0.373 mL, 0.373 mmol)and the mixture stirred in a sealed vessel at rt for 1 h. The reactionmixture was quenched with water (5 mL) and extracted with EtOAc (2×5mL). The organic extracts were combined, dried through a hydrophobicfrit and the solvent removed under vacuum. The residue was loaded inCHCl₃ (3 mL) and purified on a 100 g silica cartridge using a gradientof 0-15% MeOH in DCM. All collected fractions were combined and thesolvent removed by rotary evaporation to give ˜150 mg of a yellow gum.This was dissolved in 1:1 DMSO:MeOH (2 mL) and purified by MDAP (HpH)(2×1 mL runs). The appropriate fractions from both runs were combinedand the solvent removed by rotary evaporation to give the product as anoff-white solid (75 mg, 0.242 mmol, 68%).

LCMS (2 min Formic): Rt=0.94 min, [MH]⁺=311.

Intermediate 30: rac-benzyl((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 12, 411 mg, 0.99 mmol) in anhydrousdichloromethane (DCM) (6 mL) under nitrogen was added pyridine (0.24 mL,2.97 mmol) followed by propionyl chloride (0.125 mL, 1.486 mmol). Thereaction mixture was stirred at rt under nitrogen for 17 h. The reactionmixture was applied directly to a 25 g silica cartridge and was purifiedby flash column chromatography eluting with a gradient of 0-40% ethylacetate in cyclohexane. The required fractions were combined andevaporated in vacuo to give the desired product as a white crunchy foam(401 mg, 0.85 mmol, 86%). LCMS (2 min Formic): Rt=1.26 min, [MH]⁺=471,473.

Intermediate 31:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one

rac-Benzyl((2S,3R,4R)-2-cyclopropyl-3-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(90 mg, 0.229 mmol) was dissolved in ethanol (5 mL). Ammonium formate(145 mg, 2.293 mmol) and 10% Pd/C (20 mg, 0.188 mmol) were added andreaction mixture heated at reflux. The reaction mixture was cooled to rtand filtered through a celite cartridge. The reaction mixture wasconcentrated in vacuo and loaded onto a 2 g SCX cartridge(pre-conditioned with MeOH). This was eluted with MeOH (35 mL) followedby 2M NH₃ in MeOH (35 mL). Ammonia fractions were combined andconcentrated to give the product (58 mg, 0.224 mmol, 98%) as a paleyellow oil.

LCMS (2 min Formic): Rt=0.57 min, [M]⁺=242 (loss of NH₂ ⁻).

Intermediate 32: N-allyl-N-methylaniline

To a suspension of N-methylaniline (1.01 ml, 9.33 mmol) and potassiumhydroxide (1.05 g, 18.66 mmol) in acetonitrile (34.7 mL) stirred undernitrogen at rt was added 3-bromoprop-1-ene (1.62 mL, 18.66 mmol). Thereaction mixture was stirred at 50° C. for 7 h. The reaction mixture wasquenched with water, partitioned between ethyl acetate (25 mL) and water(50 mL). The aqueous layer was washed with ethyl acetate (50 mL) and thecombined organics dried over magnesium sulphate and evaporated in vacuoto give the crude product as a yellow oil. The crude product was addedto a silica gel column and was eluted with 0-3% EtOAc/cyclohexane. Purefractions were evaporated to afford N-allyl-N-methylaniline (80 mg, 0.53mmol, 5.7%) as a colourless oil. Impure fractions were evaporated toafford as second batch of N-allyl-N-methylaniline (730 mg, 4.46 mmol,48%) as a yellow oil (90% pure). LCMS (2 min HpH): Rt=1.22 min,[MH]⁺=148.

Intermediate 33: (E)-N-methyl-N-(prop-1-en-1-yl)aniline

A solution of N-allyl-N-methylaniline (for a preparation seeIntermediate 32, 300 mg, 2.04 mmol) andtris(triphenylphosphine)rhodium(I) carbonyl hydride (46.8 mg, 0.05 mmol)in dry tetrahydrofuran (THF) (1.56 mL) was stirred at 60° C. in a sealedvessel under an atmosphere of nitrogen for 2 h. The reaction wasincomplete so further tris(triphenylphosphine)rhodium(I) carbonylhydride (46.8 mg, 0.05 mmol) was added and the reaction stirred at 60°C. for 3 h. The reaction was cooled to rt and triethylamine (0.01 mL,0.07 mmol) added. Pentane (5 mL) was added and the mixture was cooled to−70° C. Rhodium and phosphine impurities precipitated and the mixturewas filtered. The solvent was removed under vacuum to afford a yellowoil (280 mg, 1.62 mmol, 79%). This was used immediately withoutpurification. LCMS (2 min HpH): Rt=1.31 min, [MH]⁺=not observed.

Intermediate 34:rac-(2S,3S,4R)-2-cyclopropyl-N,3-dimethyl-N-phenyl-1,2,3,4-tetrahydroquinolin-4-amine

Under an atmosphere of nitrogen, to a solution of aniline (147 μl, 1.62mmol) and 3A molecular sieves in dry dichloromethane (DCM) (5 mL) in aheat-dried flask was added cyclopropanecarbaldehyde (133 μl, 1.78 mmol).The mixture was stirred at rt for 2 h then cooled to −78° C. To thesolution was added diphenyl hydrogen phosphate (40.4 mg, 0.162 mmol) indry dichloromethane (DCM) (1.5 mL) followed by(E)-N-methyl-N-(prop-1-en-1-yl)aniline (for a preparation seeIntermediate 33, 280 mg, 1.617 mmol) in dry dichloromethane (DCM) (1.5mL). The solution was stirred at −78° C. for 3 h then warmed to rt andstirred 2 h. The reaction mixture was filtered and diluted with DCM (5mL) and NaHCO₃ (10 mL). The aqueous layers were washed with DCM (2×20mL), the combined organics dried through a hydrophobic frit and thesolvent removed by rotary evaporation. Crude material was purified on a100 g silica cartridge using a gradient of 0-20% EtOAc in cyclohexane.Fractions were evaporated to dryness and the residue triturated withMeOH to afford the required product (115 mg, 0.39 mmol, 24%) as a whitesolid.

LCMS (2 min Formic): Rt=1.49 min, [M]⁺=186 (loss of PhNMe⁻).

Intermediate 35: rac-benzyl((2S,3S,4R)-6-methoxy-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of acetaldehyde (1.4 mL, 24.95 mmol) in dichloromethane(DCM) (100 mL) was added 4-methoxyaniline (3.00 g, 24.36 mmol). Thereaction mixture was stirred at rt under nitrogen for 30 minutes beforediphenyl hydrogen phosphate (0.61 g, 2.438 mmol) was added and themixture cooled to 0° C. (ice bath). A solution of (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 5.15 g,26.9 mmol) in dichloromethane (DCM) (30 mL) was added to the mixture.The reaction mixture was stirred at 0° C. under nitrogen for 1 h beforebeing allowed to warm to rt and stirred for a further 18 h. The mixturewas heated at reflux for 4 h. The mixture was cooled to 0° C. again (icebath) and acetaldehyde (14.0 mL, 249 mmol) was added. After stirring at0° C. for 1 h the cooling bath was removed and the reaction was allowedto warm to rt and stirred for a further 24 h after which it was left tostand for 12.5 days. The volatiles were evaporated in vacuo and theresidue was re-dissolved in dichloromethane (ca. 20 mL) and was loadedonto a 100 g silica SPE cartridge. The cartridge was eluted with agradient of 0-50% ethyl acetate in cyclohexane and the requiredfractions were combined and evaporated in vacuo to give the desiredproduct which was further purified on a 50 g silica SPE cartridgeeluting with a gradient of 0-10% ethyl acetate in dichloromethane. Therequired fractions were combined and evaporated in vacuo to give thedesired product as a brown solid (903 mg, 2.65 mmol, 11%).

LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=341.

Intermediate 36: rac-benzyl((2S,3R,4R)-1-acetyl-6-methoxy-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-6-methoxy-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 35, 0.903 g, 2.65 mmol) in anhydrousdichloromethane (DCM) (20 mL) under nitrogen was added pyridine (0.64mL, 7.96 mmol) followed by acetyl chloride (0.28 mL, 3.98 mmol). Thereaction mixture was stirred under nitrogen at rt for 2.5 h. Thereaction mixture had saturated aqueous sodium bicarbonate solution (50mL) added and the phases were separated. The aqueous phase was extractedwith further dichloromethane (2×50 mL). The organic phases werecombined, dried by passing through a hydrophobic frit and the solventevaporated in vacuo to give a dark purple oil. The residue was dissolvedin dichloromethane (˜8 mL) and was purified by flash columnchromatography (50 g silica cartridge) eluting with a gradient of 0-60%ethyl acetate in cyclohexane. The required fractions were combined andthe solvent evaporated in vacuo to give the desired product as a lightbrown gum (911.9 mg, 2.384 mmol, 90%).

LCMS (2 min Formic): Rt=1.01 min, [MH]⁺=383.

Intermediate 37:rac-1-((2S,3R,4R)-4-amino-6-methoxy-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A stirred mixture of rac-benzyl((2S,3R,4R)-1-acetyl-6-methoxy-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 36, 907 mg, 2.372 mmol) and 10 wt. %(dry basis) palladium on activated carbon (wet, Degussa type E101 NE/W)(196 mg, 1.841 mmol) in ethanol (25 mL) was hydrogenated with vigorousstirring under an atmosphere of hydrogen at rt and pressure for 3.25 h.The mixture was filtered under nitrogen through a pad of celite filteraid and the filter cake washed with ethanol (3×5 mL). The combinedfiltrate was evaporated in vacuo to give the desired product as a palebrown gum (521 mg, 2.1 mmol, 89%).

LCMS (2 min Formic): Rt=0.44 min, [MH]⁺=249.

Intermediate 38: rac-benzyl((2S,3S,4R)-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of propionaldehyde (0.304 mL, 4.18 mmol) in anhydrousdichloromethane (DCM) (10 mL), was added 4-fluoroaniline (0.40 mL, 4.18mmol) and the reaction stirred at rt for 1 h. Diphenyl hydrogenphosphate (105 mg, 0.418 mmol) in anhydrous dichloromethane (DCM) (5 mL)was added and then (E)-benzyl prop-1-en-1-ylcarbamate (for a preparationsee Intermediate 1, 800 mg, 4.18 mmol) in anhydrous dichloromethane(DCM) (5 mL). The reaction was left to stir for 18 h at rt. The mixturewas diluted with DCM (15 mL) and washed with NaHCO₃ (35 mL) and thenwater (35 mL) and the organic and aqueous layers were separated. Theorganic layer was dried through a hydrophobic frit and concentrated invacuo to give 1.503 g of crude brown solid. This was purified bychromatography on silica gel (50 g) eluting with ethylacetate/cyclohexane (0-40%). The fractions containing only product werecombined and concentrated in vacuo to give the product (627 mg, 1.83mmol, 44%) as an off-white solid. LCMS (2 min Formic): Rt=1.20 min,[MH]⁺=343.

Intermediate 39: rac-benzyl((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a reaction vessel containing rac-benzyl((2S,3S,4R)-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 38, 0.54 mL, 1.831 mmol) and DIPEA(0.96 mL, 5.49 mmol) in dichloromethane (DCM) (20 mL), acetyl chloride(0.16 mL, 2.197 mmol) was added and the reaction left to stir for 16 h.A further portion of acetyl chloride (0.16 mL, 2.197 mmol) was added andthe reaction left to stir for 1 h. A further portion of acetyl chloride(0.05 mL, 0.703 mmol) was added and the reaction was left to stir for 1h. The mixture was concentrated in vacuo to give 1.85 g of crude brownsolid. This was purified by chromatography on silica gel (25 g) elutingwith 0-40% ethyl acetate/cyclohexane. The fractions containing productwere combined and concentrated in vacuo to give the product (611 mg,1.59 mmol, 87%) as a yellow solid.

LCMS (2 min Formic): Rt=1.08 min, [MH]⁺=385.

Intermediate 40:rac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 39, 611 mg, 1.59 mmol) in ethanol(40 mL), 10% Pd/C (85 mg, 0.795 mmol) was added and the reaction wasleft to stir under a hydrogen atmosphere for 2 h. The reaction mixturewas filtered through celite and the celite washed with ethyl acetate(3×20 mL). The combined filtrates were concentrated in vacuo to give theproduct (442 mg) as a yellow solid. LCMS (2 min Formic): Rt=0.47 min,[MH]⁺=251.

Intermediate 41: rac-benzyl((2S,3S,4R)-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of 3-fluoroaniline (0.91 mL, 9.00 mmol) in drydichloromethane (DCM) (11 mL) was added cyclopropanecarbaldehyde (0.67mL, 9.00 mmol). The mixture was stirred at rt under nitrogen for 60 minsthen cooled to 0° C. (ice bath). To the mixture was added first diphenylhydrogen phosphate (22.8 g, 91 mmol) in dry dichloromethane (DCM) (13mL) followed by (E)-benzyl prop-1-en-1-ylcarbamate (for a preparationsee Intermediate 1, 187.3 g, 979 mmol) in dry dichloromethane (DCM) (13mL). Stirring was continued at 0° C. and the reaction was allowed towarm to rtrt overnight. The reaction mixture was washed with 2M aqueoussodium hydroxide solution (30 mL) followed by water (30 mL). The organiclayer was dried by passing it through a hydrophobic frit and the solventwas evaporated in vacuo. The residue was re-dissolved in dichloromethane(˜10 mL) and was purified by flash column chromatography being appliedto a 100 g silica cartridge and eluted with a gradient of 0-40% ethylacetate in cyclohexane. The required fractions were combined andevaporated in vacuo to give the desired product (191 mg, 0.54 mmol, 6%).

LCMS (2 min Formic): Rt=1.29 min, [MH]⁺=355.

Intermediate 42: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 41, 190 mg, 0.536 mmol) in anhydrousdichloromethane (DCM) (15 mL) under nitrogen was added pyridine (130 μl,1.61 mmol) followed by acetyl chloride (57 μl, 0.80 mmol). The reactionmixture was stirred under nitrogen at rtrt for 90 min. The reactionmixture had saturated aqueous sodium bicarbonate solution (30 mL) addedand the phases were separated. The aqueous phase was extracted withfurther dichloromethane (3×15 mL). The organic phases were combined,dried by passing through a cartridge fitted with a hydrophobic frit andthe solvent evaporated in vacuo to give a pale brown residue. Theresidue was dissolved in dichloromethane (˜8 mL) and was purified byflash column chromatography (50 g silica cartridge) eluting with agradient of 0-60% ethyl acetate in cyclohexane. The required fractionswere combined and the solvent evaporated in vacuo to give the desiredproduct as a pale yellow solid (201 mg, 0.51 mmol, 95%). LCMS (2 minFormic): Rt=1.13 min, [MH]⁺=397.

Intermediate 43:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-7-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A stirred mixture of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 42, 201 mg, 0.51 mmol) and 10 wt. %(dry basis) palladium on activated carbon (wet, Degussa type E101 NE/W)(48.6 mg, 0.457 mmol) in ethanol (10 mL) was hydrogenated with vigorousstirring under one atmosphere of hydrogen at rtrt for 4.33 h. Thereaction mixture was filtered over celite, and the filtrate wasevaporated in vacuo to give the desired product as a gum (146 mg).

LCMS (2 min Formic): Rt=0.53 min, [M]⁺=246 (loss of NH₂ ⁻).

Intermediate 44: rac-benzyl((2S,3S,4R)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of 3-methoxyaniline (0.91 mL, 8.12 mmol) in drydichloromethane (DCM) (11 mL) was added cyclopropanecarbaldehyde (0.61mL, 8.12 mmol). The mixture was stirred at rt under nitrogen for 60 minthen cooled to 0° C. (ice bath). To the mixture was added first diphenylhydrogen phosphate (0.202 g, 0.808 mmol) in dry dichloromethane (DCM)(13 mL) followed by (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 1.7 g, 8.87 mmol) in dry dichloromethane(DCM) (13 mL). Stirring was continued at 0° C. and allowed to warm to rtovernight. The reaction mixture was washed with 2M aqueous sodiumhydroxide solution (30 mL) followed by water (30 mL). The organic layerwas dried by passing it through a cartridge fitted with a hydrophobicfrit and the solvent was evaporated in vacuo. The residue wasre-dissolved in dichloromethane (˜10 mL) and was purified by flashcolumn chromatography being applied to a 100 g silica cartridge andeluted with a gradient of 0-40% ethyl acetate in cyclohexane. Therequired fractions were combined and evaporated in vacuo to give thedesired product a white foam solid (2.254 g, 6.15 mmol, 76%). LCMS (2min Formic): Rt=1.19 min, [MH]⁺=367.

Intermediate 45: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 41, 2.25 g, 6.15 mmol) in anhydrousdichloromethane (DCM) (42 mL) under nitrogen was added pyridine (1.49mL, 18.45 mmol) followed by acetyl chloride (0.66 mL, 9.23 mmol). Thereaction mixture was stirred at rtrt under nitrogen for 2.25 h. Thereaction mixture had saturated aqueous sodium bicarbonate solution (100mL) added and the phases were separated. The aqueous phase was extractedwith further dichloromethane (3×50 mL). The organic phases werecombined, dried by passing through a hydrophobic frit and the solventevaporated in vacuo to give a dark purple oil. The residue was dissolvedin dichloromethane (˜8 mL) and was purified by flash columnchromatography (100 g silica cartridge) eluting with a gradient of 0-60%ethyl acetate in cyclohexane. The required fractions were combined andthe solvent evaporated in vacuo to give the desired product as a whitesolid (2.07 g, 5.08 mmol, 83%). LCMS (2 min Formic): Rt=1.10 min,[MH]⁺=409.

Intermediate 46:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-7-methoxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A stirred mixture of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 45, 2.07 g, 5.08 mmol) and 10 wt. %(dry basis) palladium on activated carbon (wet, Degussa type E101 NE/W)(508 mg, 4.77 mmol) in ethanol (65 mL) was hydrogenated with vigorousstirring under one atmosphere of hydrogen at rt for 2.25 h. The reactionmixture was filtered over celite, and the filtrate was transferred intoa vial and evaporated down under a stream of nitrogen to give thedesired product as a gum. The residue was dissolved in dichloromethane(˜8 mL) and was purified by flash column chromatography (50 g silicacartridge) eluting with a gradient of 0-60% ethyl acetate incyclohexane. The required fractions were combined and the solventevaporated in vacuo to give the desired product as a pale yellow solid(0.87 g, 3.19 mmol, 63%).

LCMS (2 min Formic): Rt=0.47 min, [M]⁺=258 (loss of NH₂ ⁻).

Intermediate 47: rac-benzyl((2S,3S,4R)-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The 4-aminobenzonitrile (434 mg, 3.67 mmol) was taken up in DCM (8 mL)and was treated with cyclopropanecarbaldehyde (0.288 mL, 3.86 mmol) andallowed to stir at rt for 1 h. The reaction was then cooled to 0° C. andwas treated with a solution of (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 773 mg, 4.04 mmol) in DCM (2 mL)followed by diphenyl phosphate (92 mg, 0.367 mmol), the reaction wasallowed to warm to rt and then to stir at rt for 1 h. The reaction wasconcentrated and then suspended in hot IPA. After cooling to rt a whiteprecipitate resulted which was removed by filtration and dried to givethe product (674 mg) as a white solid. This was used as was in thesubsequent reaction.

LCMS (2 min Formic): Rt=1.15 min, [MH]⁺=362.

Intermediate 48: rac-benzyl((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

rac-Benzyl((2S,3S,4R)-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 47, 674 mg, 1.865 mmol) was taken upin dichloromethane (DCM) (30 mL) and treated with DIPEA (0.65 mL, 3.73mmol) and acetyl chloride (0.4 mL, 5.59 mmol) and allowed to stir at rtfor 3 days. The reaction was concentrated and purified using a columnchromatography (10 g silica) 0-50% EtOAc:cyclohexane. The appropriatefractions were summed and concentrated to give the product (524 mg) as awhite solid.

LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=404.

Intermediate 49:rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

rac-Benzyl((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 48, 524 mg, 1.30 mmol) was suspendedin ethanol (10 mL) and was hydrogenated using the H-cube (25° C., 1 bar,1 mL/min flow rate) and a 10% Pd/C CatCart 30 as the catalyst. Thereaction mixture was concentrated and dried to give the product as acolourless gum (315 mg). LCMS (2 min Formic): Rt=0.49 min, [MH]⁺=270.

Intermediate 50: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A mixture of Pd₂(dba)₃ (30 mg, 0.033 mmol), XantPhos (40 mg, 0.069mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 13, 300 mg, 0.656 mmol) and sodiummethanethiolate (92 mg, 1.312 mmol) in a 2-5 mL microwave vessel wasdiluted with anhydrous 1,4-dioxane (2.0 mL). The vessel was sealed andheated in a microwave reactor at 140° C. for 45 min. The reactionmixture was diluted with 2M Na₂S₂O₃ (aq) (3.0 mL) and 2M NaHCO₃ (aq)(0.5 mL). The mixture was extracted with EtOAc (2×2 mL), the organicextracts were combined and dried through a hydrophobic frit. The solventwas removed under a stream of nitrogen and the residue diluted withchloroform (4 mL). The solution was cooled to 0° C., treated with3-chlorobenzoperoxoic acid (340 mg, 1.968 mmol) and stirred in astoppered vessel for 10 min. The mixture was allowed to warm to rt over3 h. The reaction mixture was washed with 10% w/v Na₂CO₃ (aq) (2×5 mL)followed by water (5 mL). The organic layer was dried through ahydrophobic frit and the solvent evaporated under a stream of nitrogento give the product (80 mg). LCMS (2 min Formic): Rt=0.98 min,[MH]⁺=457.

Intermediate 51:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-(methylsulfonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-Benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 50, 80 mg, 0.175 mmol) in methanol(3.5 mL) was hydrogenated using the H-cube (rt, full H₂ mode, 1 mL/minflow rate) and 10% Pd/C as catalyst. The solvent was evaporated in vacuoto give the product (51 mg, 0.159 mmol, 91% yield). LCMS (2 min Formic):Rt=0.47 min, [M]⁺=306 (loss of NH₂ ⁻).

Intermediate 52: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(isopropylsulfonyl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A mixture of Pd₂(dba)₃ (30 mg, 0.033 mmol), XantPhos (40 mg, 0.069 mmol)and rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 13, 300 mg, 0.656 mmol) in a 0.5-2mL microwave vessel was diluted with anhydrous 1,4-dioxane (2 mL) andtreated with DIPEA (0.230 mL, 1.317 mmol) followed by propane-2-thiol(0.120 mL, 1.292 mmol). The vessel was sealed and heated in a microwavereactor at 140° C. for 45 min. The reaction mixture was diluted with 2MNa₂S₂O₃ (aq) (3 mL) and 2M NaHCO₃ (aq) (0.5 mL). The mixture wasextracted with EtOAc (2×2 mL), the organic extracts were combined anddried through a hydrophobic frit. The solvent was removed under a streamof nitrogen and the residue diluted with chloroform (2 mL). The solutionwas treated with 3-chlorobenzoperoxoic acid (170 mg, 0.985 mmol) andleft to stand in a stoppered vessel at rt for 1.5 h. Further3-chlorobenzoperoxoic acid (215 mg, 1.246 mmol) was added and thereaction was left to stand at rt for 16 h during which time the mixturesolidified. The reaction mixture was diluted with CHCl₃ (3 mL) andwashed with 10% w/v Na₂CO₃ (aq) (2×5 mL) followed by water (5 mL). Theorganic layer was dried through a hydrophobic frit and the solventevaporated under a stream of nitrogen. The residue was loaded in DCM (5mL) and purified on a 50 g silica cartridge using a gradient of 0-100%EtOAc in cyclohexane. The appropriate fractions were combined and thesolvent removed by rotary evaporation to give the product as a lightyellow gum (293 mg, 0.605 mmol, 92%).

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=484.

Intermediate 53:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(isopropylsulfonyl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(isopropylsulfonyl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 52, 288 mg, 0.594 mmol) in methanol(12 mL) was hydrogenated using the H-cube (rt, full H₂ mode, 1 mL/minflow rate) and a 10% Pd/C CatCart 30 as the catalyst. The eluent wasconcentrated in vacuo to −12 mL and passed through the H-Cube using thesame conditions for a second time. The eluent was concentrated in vacuoto ˜12 mL and passed through the H-Cube using the same conditions butwith a fresh CatCart. The eluent was evaporated in vacuo to give theproduct as a light yellow gum (169 mg, 0.482 mmol, 81%). LCMS (2 minHpH): Rt=0.80 min, [M]⁺=334 (loss of NH₂ ⁻).

Intermediate 54: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (73.8 mg, 0.396mmol) in 1,4-dioxane (3 mL) were added rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 142.4 mg, 0.330 mmol), DavePhos(12.99 mg, 0.033 mmol), Pd₂(dba)₃ (15.12 mg, 0.017 mmol) and sodiumtert-butoxide (47.6 mg, 0.495 mmol). The reaction was irradiated in amicrowave at 110° C. for 30 min. The reaction mixture was filteredthrough a pad of celite (rinsed with EtOAc). The filtrate was thenevaporated in vacuo and purified by chromatography on silica gel elutingwith 0-100% of ethyl acetate in cyclohexane. Then the column was flushedwith 10% of methanol in DCM to give crude product which was furtherpurified by chromatography on silica gel eluting with 0-10% of methanolin DCM to the product (55 mg, 41%) as a yellow solid.

LCMS (2 min Formic): Rt=0.66 min, [M]⁺=386 (loss of NH₂ ⁻).

Intermediate 55: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

Under nitrogen atmosphere, to a solution of bromobenzene (0.020 mL,0.191 mmol) in 1,4-dioxane (3 mL) were added rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 54, 64 mg, 0.159 mmol), DavePhos(6.26 mg, 0.016 mmol), Pd₂(dba)₃ (7.28 mg, 7.95 μmol) and sodiumtert-butoxide (22.92 mg, 0.238 mmol). The reaction was irradiated at110° C. for 1 h. The reaction was treated with further Pd₂(dba)₃ (7.28mg, 7.95 μmol), DavePhos (6.26 mg, 0.016 mmol) and sodium tert-butoxide(22.92 mg, 0.238 mmol) and irradiated at 110° C. for 30 min. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo andpurified by MDAP (Formic) to give the product (24 mg, 32%) as a yellowsolid. LCMS (2 min Formic): Rt=1.26 min, [MH]⁺=479.

Intermediate 56: rac1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of morpholine (0.034 mL, 0.389 mmol) in 1,4-dioxane (3 mL)were added rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 139.7 mg, 0.324 mmol), DavePhos(12.75 mg, 0.032 mmol), Pd₂(dba)₃ (14.83 mg, 0.016 mmol) and sodiumtert-butoxide (46.7 mg, 0.486 mmol). The reaction was irradiated at 110°C. for 30 min. The reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated and purified bycolumn chromatography on silica gel eluting with 0-10% of methanol inDCM to give the product (33 mg, 33%) as a white solid.

LCMS (2 min Formic): Rt=0.44 min, [MH]⁺=304.

Intermediate 57: tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a greenhouse test tube was added rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(fora preparation see Intermediate 3, 101 mg, 0.234 mmol), sodiumtert-butoxide (65 mg, 0.676 mmol), DavePhos (18.1 mg, 0.046 mmol),Pd₂(dba)₃ (21.9 mg, 0.024 mmol) and 1,4-dioxane (2 mL). tert-Butyl2-methylpiperazine-1-carboxylate (0.070 mL, 0.351 mmol) was then addedand the reaction mixture stirred at 100° C. for 20 h 45 min. Thereaction mixture was allowed to cool to rt and then filtered through apad of celite and rinsed with ethyl acetate. The filtrate wasconcentrated and purified by MDAP (Formic) to give the product (14.1 mg,0.034 mmol, 14.46%) as a pale yellow gum. This was a racemic mixture ofdiatereoisomers. LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=417.

Intermediate 58: tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a greenhouse test tube was added tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 57, 14.1 mg, 0.034 mmol),bromobenzene (5 μL, 0.047 mmol), Pd₂(dba)₃ (2.2 mg, 2.402 μmol),DavePhos (1.6 mg, 4.07 μmol), sodium tert-butoxide (5.1 mg, 0.053 mmol)and 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 100° C.under nitrogen for 16 h. The reaction mixture was allowed to cool to rtthen loaded onto a 2.5 g celite cartridge, eluted with ethyl acetatethen evaporated under a stream of nitrogen. To the residue was added1,4-dioxane (0.5 mL), DavePhos (1.8 mg, 4.57 μmol), Pd₂(dba)₃ (2.1 mg,2.293 μmol), sodium tert-butoxide (5.7 mg, 0.059 mmol) and bromobenzene(5 μL, 0.047 mmol). The reaction mixture was stirred at 100° C. undernitrogen for a further 4 h. The reaction mixture was allowed to cool tort then loaded onto a 2.5 g celite cartridge, eluted with ethyl acetatethen concentrated and purified by MDAP (Formic) to give the product (7.4mg, 0.015 mmol, 44.4%) as a yellow gum. This was a racemic mixture ofdiatereoisomers. LCMS (2 min Formic): Rt=1.32 min, [MH]⁺=493.

Intermediate 59: rac-tert-butyl(1-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-4-yl)carbamate

To a solution of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 148.7 mg, 0.345 mmol) in1,4-dioxane (3 mL) were added tert-butyl piperidin-4-ylcarbamate (83 mg,0.414 mmol), Pd₂(dba)₃ (15.78 mg, 0.017 mmol), DavePhos (13.57 mg, 0.034mmol) and sodium tert-butoxide (49.7 mg, 0.517 mmol). The reaction wasirradiated in a microwave at 110° C. for 30 min. After cooling to rt,the reaction mixture was filtered through a pad of celite (rinsed withEtOAc). The filtrate was then evaporated in vacuo and purified by columnchromatography on silica gel eluting with 0-100% of ethyl acetate incyclohexane to give the product (29.2 mg, 15%) as a yellow solid.

LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=551.

Intermediate 60: rac-tert-butyl(1-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-4-yl)carbamate

rac-tert-Butyl(1-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-4-yl)carbamate(for a preparation see Intermediate 59, 29.2 mg, 0.053 mmol) wasdissolved in methanol (2 mL) and was then passed through a 10% Pd/Ccartridge on a H-cube (rt, full H₂ mode) to give a colourless filtrate.This filtrate was concentrated in vacuo to give the product (15 mg) as acolourless solid.

LCMS (2 min Formic): Rt=0.70 min, [M]⁺=400 (loss of NH₂ ⁻).

Intermediate 61: rac-tert-butyl(1-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-4-yl)carbamate

Under nitrogen atmosphere, to a solution of bromobenzene (4.63 μL, 0.043mmol) in 1,4-dioxane (1 mL) were added rac-tert-butyl(1-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-4-yl)carbamate(for a preparation see Intermediate 60, 15.1 mg, 0.036 mmol), DavePhos(1.427 mg, 3.62 μmol), Pd₂(dba)₃ (1.660 mg, 1.812 μmol) and sodiumtert-butoxide (5.23 mg, 0.054 mmol). The reaction mixture was degassedwith nitrogen for 10 min and irradiated in a microwave at 110° C. for 30min. The reaction was treated with further bromobenzene (4.63 μL, 0.043mmol), Pd₂(dba)₃ (1.660 mg, 1.812 μmol), DavePhos (1.427 mg, 3.62 μmol)and sodium tert-butoxide (5.23 mg, 0.054 mmol) and irradiated in amicrowave at 110° C. for 30 min. After cooling to rt, the reactionmixture was filtered through a pad of celite (rinsed with EtOAc). Thefiltrate was then evaporated in vacuo and the residue purified bychromatography on silica gel eluting with 0-100% of ethyl acetate incyclohexane to give the product (6.8 mg, 38%) as a colourless solid.LCMS (2 min Formic): Rt=1.14 min, [MH]⁺=493.

Intermediate 62: rac-tert-butyl4-(((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (84 mg,0.417 mmol) in 1,4-dioxane (3 mL) were added rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(150 mg, 0.348 mmol), DavePhos (13.69 mg, 0.035 mmol), Pd₂(dba)₃ (15.92mg, 0.017 mmol) and sodium tert-butoxide (50.1 mg, 0.522 mmol). Thereaction was irradiated in a microwave at 110° C. for 30 min. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo andpurified by chromatography on silica gel eluting with 0-100% of ethylacetate in cyclohexane to give the product (19 mg, 10%) as a yellowsolid. LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=495

Intermediate 63: rac-tert-butyl4-(((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)piperidine-1-carboxylate

rac-tert-butyl4-(((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)piperidine-1-carboxylate(for a preparation see Intermediate 62, 19 mg, 0.035 mmol) was dissolvedin methanol (2 mL) and was then passed through a 10% Pd/C cartridge on aH-cube (rt, full H₂ mode) to give a colourless filtrate. This filtratewas concentrated in vacuo to give the product (12 mg, 86%) as acolourless solid.

LCMS (2 min Formic): Rt=0.74 min, [M]⁺=400 (loss of NH₂ ⁻).

Intermediate 64: rac-tert-butyl4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)amino)piperidine-1-carboxylate

Under nitrogen atmosphere, to a solution of bromobenzene (3.77 μL, 0.035mmol) in 1,4-dioxane (1 mL) were added rac-tert-butyl4-(((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)piperidine-1-carboxylate(for a preparation see Intermediate 63, 12.3 mg, 0.030 mmol), DavePhos(1.162 mg, 2.95 μmol), Pd₂(dba)₃ (1.352 mg, 1.476 μmol) and sodiumtert-butoxide (4.26 mg, 0.044 mmol). The reaction mixture was degassedwith nitrogen for 10 min and irradiated in a microwave at 110° C. for 30min. The reaction was treated with further bromobenzene (3.77 μL, 0.035mmol), Pd₂(dba)₃ (1.352 mg, 1.476 μmol), DavePhos (1.162 mg, 2.95 μmol)and sodium tert-butoxide (4.26 mg, 0.044 mmol) and irradiated in amicrowave at 110° C. for 30 min. After cooling to rt, the reactionmixture was filtered through a pad of celite (rinsed with EtOAc). Thefiltrate was then evaporated in vacuo and purified by chromatography onsilica gel eluting with 0-100% of ethyl acetate in cyclohexane to givethe product (11 mg, 74%) as a yellow solid. LCMS (2 min Formic): Rt=1.13min, [MH]⁺=493.

Intermediate 65:1-((rac-2S,3R,4R)-4-amino-2,3-dimethyl-6-(2-methylmorpholino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a tube was added 2-methylmorpholine (23.0 mg, 0.227 mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 62.6 mg, 0.145 mmol), sodiumtert-butoxide (42.6 mg, 0.443 mmol), DavePhos (12.0 mg, 0.030 mmol,Pd₂(dba)₃ (13.0 mg, 0.014 mmol) and 1,4-dioxane (2 mL). The reactionmixture was stirred at 100° C. under nitrogen for 19 h. The reactionmixture was allowed to cool to rt then loaded onto a 2.5 g celitecartridge, eluted with ethyl acetate then evaporated under a stream ofnitrogen. The residue was purified MDAP (Formic) to give the product(5.9 mg, 0.019 mmol, 12.81%) as a pale yellow gum. This was a racemicmixture of diatereoisomers.

LCMS (2 min Formic): Rt=0.52 min, [MH]⁺=318.

Intermediate 66: tert-butyl5-((rac-2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate

A mixture of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 73.5 mg, 0.170 mmol), tert-butyl2,5-diazabicyclo[2.2.2]octane-2-carboxylate (43.8 mg, 0.206 mmol),sodium-tert-butoxide (49.4 mg, 0.514 mmol), DavePhos (13.6 mg, 0.035mmol) and Pd₂(dba)₃ (15.5 mg, 0.017 mmol) had 1,4-dioxane (2 mL) addedand were heated with stirring under nitrogen at 100° C. The reactionmixture was allowed to cool to rt and filtered through a celitecartridge which was flushed with ethyl acetate, the filtrate wasconcentrated and purified by MDAP (Formic) to give the product (12.9 mg,0.030 mmol, 17.66%) as a cream solid. This was a racemic mixture ofdiatereoisomers.

LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=429.

Intermediate 67: tert-butyl5-((rac-2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(Phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate

To a solution of tert-butyl5-((rac-2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate(for a preparation see Intermediate 66, 12.9 mg, 0.030 mmol) in1,4-dioxane (0.5 mL) was added bromobenzene (5 μL, 0.047 mmol),Pd₂(dba)₃ (1.4 mg, 1.529 μmol), DavePhos (1.2 mg, 3.05 μmol) and sodiumtert-butoxide (4.2 mg, 0.044 mmol). The reaction mixture was stirred at100° C. for 18 h. The reaction mixture was allowed to cool to rt thenloaded onto a 2.5 g celite cartridge, eluted with ethyl acetate thenevaporated under a stream of nitrogen. To the residue was added1,4-dioxane (0.5 mL), bromobenzene (10 μL, 0.094 mmol), Pd₂(dba)₃ (2.1mg, 2.293 μmol), DavePhos (2.3 mg, 5.84 μmol) and sodium tert-butoxide(4.6 mg, 0.048 mmol). The reaction mixture was stirred at 100° C. for afurther 21 h. The reaction mixture was allowed to cool to rt then loadedonto a 2.5 g celite cartridge, eluted with ethyl acetate then evaporatedunder a stream of nitrogen. To the residue was added 1,4-dioxane (0.5mL), bromobenzene (10 μL, 0.094 mmol), Pd₂(dba)₃ (2.0 mg, 2.184 μmol),DavePhos (2.2 mg, 5.59 μmol) and sodium tert-butoxide (4.4 mg, 0.046mmol). The reaction mixture was stirred at 100° C. for a further 6 h.The reaction mixture was allowed to cool to rt then loaded onto a 2.5 gcelite cartridge, eluted with ethyl acetate then evaporated under astream of nitrogen. The residue was purified by MDAP (Formic) to givethe product (4.7 mg, 9.31 μmol, 30.9%). This was a racemic mixture ofdiatereoisomers. LCMS (2 min Formic): Rt=1.30 min, [MH]⁺=505.

Intermediate 68:rac-1-((2S,3R,4R)-4-amino-6-(-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 75.3 mg, 0.175 mmol),(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane, hydrochloride (32.3 mg, 0.216mmol), sodium-tert-butoxide (68.4 mg, 0.712 mmol), DavePhos (14.6 mg,0.037 mmol) and Pd₂(dba)₃ (17.1 mg, 0.019 mmol) had 1,4-dioxane (2 mL)added and were heated with stirring under nitrogen at 100° C. for 23 h.The reaction mixture was allowed to cool to rt and filtered through acelite cartridge which was flushed with ethyl acetate. The combinedfiltrates were concentrated and purified by MDAP (Formic) to give theproduct (5.6 mg, 0.017 mmol, 9.74%) as a pale yellow gum.

LCMS (2 min Formic): Rt=0.54 min, [MH]⁺=330.

Intermediate 69:1-((rac-2S,3R,4R)-4-amino-2,3-dimethyl-6-(3-methylpyrrolidin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was added rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 102.7 mg, 0.238 mmol), sodiumtert-butoxide (86.1 mg, 0.896 mmol), DavePhos (18.1 mg, 0.046 mmol),Pd₂(dba)₃ (21.7 mg, 0.024 mmol) and 1,4-dioxane (2 mL).3-methylpyrrolidine hydrochloride (42.3 mg, 0.348 mmol) was then addedand the reaction mixture stirred at 100° C. under nitrogen for 20 h 45min. The reaction mixture was allowed to cool to rt and then filteredthrough a pad of celite and rinsed with ethyl acetate. The filtrate wasconcentrated and purified by MDAP (Formic) to give the product (25.7 mg,0.085 mmol, 35.8%) as a yellow gum. This was a racemic mixture ofdiatereoisomers.

LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=302.

Intermediate 70:1-((rac-2S,3R,4R)-4-amino-2,3-dimethyl-6-(2-methylpyrrolidin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was added rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 103.2 mg, 0.239 mmol), sodiumtert-butoxide (66.1 mg, 0.688 mmol), DavePhos (19.1 mg, 0.049 mmol),Pd₂(dba)₃ (21.2 mg, 0.023 mmol) and 1,4-dioxane (2 mL).2-Methylpyrrolidine (0.037 mL, 0.359 mmol) was then added and thereaction mixture stirred at 100° C. under nitrogen for 20 h 45 min. Thereaction mixture was allowed to cool to rt and then filtered through apad of celite and rinsed with ethyl acetate. The filtrate wasconcentrated and purified by MDAP (Formic) to give the product (17.5 mg,0.058 mmol, 24.26%) as a yellow gum. This was a racemic mixture ofdiatereoisomers.

LCMS (2 min Formic): Rt=0.63 min, [MH]⁺=302.

Intermediate 71: rac-tert-butyl3-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A mixture of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, (74.8 mg, 0.173 mmol), tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate (43.1 mg, 0.203 mmol),sodium-tert-butoxide (50.8 mg, 0.529 mmol), DavePhos (14.0 mg, 0.036mmol) and Pd₂(dba)₃ (16.3 mg, 0.018 mmol) had 1,4-dioxane (2 mL) addedand were heated with stirring under nitrogen at 100° C. for 23 h. Thereaction mixture was allowed to cool to rt and filtered through a celitecartridge which was flushed with ethyl acetate. The filtrate wasconcentrated and purified by MDAP (Formic) to give the product (5.5 mg,0.013 mmol, 7.40%) as a yellow gum. LCMS (2 min Formic): Rt=0.80 min,[MH]⁺=429.

Intermediate 72: rac-tert-butyl3-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(Phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of rac-tert-butyl3-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(for a preparation see Intermediate 71, 5.5 mg, 0.013 mmol) in1,4-dioxane (0.5 mL) was added bromobenzene (5 μL, 0.047 mmol),Pd₂(dba)₃ (1.4 mg, 1.529 μmol), DavePhos (1.2 mg, 3.05 μmol) and sodiumtert-butoxide (3.1 mg, 0.032 mmol). The reaction mixture was stirred at100° C. for 18 h. The reaction mixture was allowed to cool to rt thenloaded onto a 2.5 g celite cartridge, eluted with ethyl acetate thenevaporated under a stream of nitrogen. To the residue was added1,4-dioxane (0.5 mL), bromobenzene (10 μL, 0.094 mmol), Pd₂(dba)₃ (2.1mg, 2.293 μmol), DavePhos (1.8 mg, 4.57 μmol) and sodium tert-butoxide(3.1 mg, 0.032 mmol). The reaction mixture was heated at 100° C. for afurther 21 h. The reaction mixture was allowed to cool to rt then loadedonto a 2.5 g celite cartridge, eluted with ethyl acetate then evaporatedunder a stream of nitrogen. The residue was purified by MDAP (Formic) togive the product (3.3 mg, 6.54 μmol, 51.0%).

LCMS (2 min Formic): Rt=1.33 min, [MH]⁺=505.

Intermediate 73:rac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 9, 499 mg, 1.120 mmol) in1,4-dioxane (15 mL) was added sodium tert-butoxide (324.7 mg, 3.38mmol), DavePhos (88.1 mg, 0.224 mmol), Pd₂(dba)₃ (102.1 mg, 0.111 mmol)and morpholine (0.146 mL, 1.687 mmol). The reaction mixture was stirredunder nitrogen at 100° C. for 2 h. The reaction mixture was allowed tocool to rt and then filtered through a pad of celite and washed withethyl acetate and methanol. The filtrate was evaporated in vacuo and theresidue purified by column chromatography on silica gel eluting with0-5% methanol:DCM to give a yellow gum which was further purified byMDAP (HpH) to give the product (130 mg, 0.410 mmol, 36.6%) as a yellowgum.

LCMS (2 min Formic): Rt=0.50 min, [MH]⁺=318.

Intermediate 74: (E)-tert-butyl prop-1-en-1-ylcarbamate

The tert-butyl allylcarbamate (4.3 g, 27.4 mmol) was placed in amicrowaveable vial along with tris(triphenylphosphine)rhodium(I)carbonylhydride (0.628 g, 0.684 mmol) and tetrahydrofuran (THF) (15 mL),nitrogen was bubbled through and the vial sealed and irradiated in abiotage microwave at 80° C. for 2 h. The reaction was treated withtriethylamine (0.191 mL, 1.368 mmol) and cooled to −70° C., the reactionwas filtered at this temperature and then concentrated in vacuo to givea brown oil. This oil was purified by chromatography on silica geleluting with 0-5% EtOAc:cyclohexane to give the product (2.875 g, 67%)as a yellow solid (2.875 g).

LCMS (2 min Formic): Rt=0.95 min, [MH]⁺ not observed.

Intermediate 75: rac-tert-butyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The 4-bromoaniline (750 mg, 4.36 mmol) was taken up in DCM (8 mL) andwas treated with cyclopropanecarbaldehyde (321 mg, 4.58 mmol) andallowed to stir at rt for 1 h. The reaction was then cooled to 0° C. andwas treated with a solution of (E)-tert-butyl prop-1-en-1-ylcarbamate(for a preparation see Intermediate 74, 754 mg, 4.80 mmol) in DCM (2 mL)followed by diphenyl phosphate (109 mg, 0.436 mmol), the reaction wasallowed to warm to rt and stir at rt for 3 days. The reaction wasconcentrated and purified by chromatography on silica gel eluting with0-50% EtOAc;cyclohexane to give the product (487 mg, 29%) as an offwhite solid.

LCMS (2 min Formic): Rt=1.32 min, [MH]⁺=381, 383.

Intermediate 76: rac-tert-butyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The rac-tert-butyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 75, 567 mg, 1.487 mmol) was taken upin dichloromethane (DCM) (10 mL) and treated with DIPEA (0.519 mL, 2.97mmol) and acetyl chloride (0.211 mL, 2.97 mmol) and allowed to stir atrt for 3 days. Further acetyl chloride (0.211 mL, 2.97 mmol) was addedand the reaction was allowed to stir at rt for 2 h. The reaction wasconcentrated to a gum and purified by chromatography on silica geleluting with 0-25% EtOAc:cyclohexane to give the product (589 mg, 93%)as a white solid. LCMS (2 min Formic): Rt=1.20 min, [MH]⁺=423, 425.

Intermediate 77: rac-tert-butyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(59.5 mg, 0.283 mmol), rac-tert-butyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 76, 80 mg, 0.189 mmol) and cesiumcarbonate (185 mg, 0.567 mmol) were suspended in 1,4-dioxane (10mL):water (1 mL) and treated withtetrakis(triphenylphosphine)palladium(0) (21.84 mg, 0.019 mmol). Thereaction was allowed to stir at 80° C. under reflux conditions for 5 h.The reaction was allowed to cool to rt and was partitioned between EtOAcand water, the organic layer was washed with brine, dried using ahydrophobic frit and concentrated to a gum. This gum was purified bychromatography on silica gel eluting with 0-50% EtOAc:cyclohexane togive the product (42 mg, 52%) as a colourless gum.

LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=427.

Intermediate 78:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

The rac-tert-butyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 77, 98 mg, 0.230 mmol) was taken upin dichloromethane (DCM) (5 mL), treated with TFA (0.177 mL, 2.298 mmol)and allowed to stir at rt for 18 h. The reaction was concentrated andpassed through a NH₂ SPE (1 g) eluting with MeOH. The MeOH fraction wasconcentrated and dried to give the product (56 mg, 75%) as a colourlessgum. LCMS (2 min Formic): Rt=0.59 min, [MH]⁺=327.

Intermediate 79: tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a microwave vial tert-butyl 2-methylpiperazine-1-carboxylate (0.158mL, 0.787 mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 13, 300 mg, 0.656 mmol), sodiumtert-butoxide (126 mg, 1.312 mmol), Pd₂(dba)₃ (30.0 mg, 0.033 mmol), andDavePhos (25.8 mg, 0.066 mmol) were added in 1,4-dioxane (4 mL). Thevessel was sealed and heated to 100° C. for 30 min in a microwave. Thereaction mixture was diluted with ethyl acetate (15 mL) and filteredthrough celite. The celite was washed with ethyl acetate and thecombined filtrates were concentrated in vacuo to a red/brown oil. Thisoil was purified by chromatography on silica gel eluting with 0-40%ethyl acetate/cyclohexane. Then with 0-8% 2M ammonia inmethanol:dichloromethane to give the product (92 mg, 0.208 mmol, 31.7%).This was a racemic mixture of diatereoisomers.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=443.

Intermediate 80: tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a reaction vessel tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 79,119 mg, 0.269 mmol),2-bromo-6-methylpyridine (0.061 mL, 0.538 mmol), sodium tert-butoxide(64.6 mg, 0.672 mmol), Pd₂(dba)₃ (24.62 mg, 0.027 mmol) and DavePhos(15.87 mg, 0.040 mmol) were added in 1,4-dioxane (5 mL). The reactionmixture was stirred and heated to 100° C. under nitrogen for 16 h. Thereaction was treated with further Pd₂(dba)₃ (25 mg, 0.027 mmol), sodiumtert-butoxide (65 mg, 0.676 mmol), DavePhos (20 mg, 0.051 mmol), and2-bromo-6-methylpyridine (0.06 mL, 0.527 mmol) and the reaction was leftto stir for 3.5 h at 100° C. Further sodium tert-butoxide (63 mg, 0.656mmol) was added and the reaction left to stir for 1.5 h at 100° C.Further sodium tert-butoxide (25.8 mg, 0.269 mmol) and2-bromo-6-methylpyridine (0.08 mL, 0.703 mmol) were added and thereaction left to stir for 24 h at 100° C. The cooled reaction wasfiltered through celite, concentrated and by chromatography on silicagel eluting with 0-75% ethyl acetate/cyclohexane to give crude product.This was purified by chromatography on silica gel eluting with 0-60%ethyl acetate/cyclohexane to give the product (34 mg, 23.69%) as ayellow gum. This was a racemic mixture of diatereoisomers. LCMS (2 minFormic): Rt=1.05 min, [MH]⁺=534.

Intermediate 81: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

The tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(287 mg, 0.928 mmol),rac-1-((2R,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 126, 200 mg, 0.619 mmol) and cesiumcarbonate (605 mg, 1.856 mmol) were suspended in 1,4-dioxane (10mL):water (1 mL) and treated withtetrakis(triphenylphosphine)palladium(0) (71.5 mg, 0.062 mmol). Thereaction was allowed to stir at 80° C. for 16 h. The reaction waspartitioned between water and EtOAc, the aqueous layer was extractedwith EtOAc and the combined organics were washed with brine, dried usinga hydrophobic frit and concentrated to a orange oil. This oil waspurified by chromatography on silica gel eluting with 0-100%EtOAc:cyclohexane, and then 0-10% MeOH:DCM to give the product (128 mg,49%) as a yellow oil. LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=426.

Intermediate 82: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

The 2-chloro-6-methylpyridine (77 mg, 0.602 mmol), rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 81, 128 mg, 0.301 mmol), DavePhos(11.84 mg, 0.030 mmol), Pd₂(dba)₃ (41.3 mg, 0.045 mmol), sodiumtert-butoxide (87 mg, 0.902 mmol) and 1,4-dioxane (10 mL) were placed ina round bottomed flask and allowed to stir at 100° C. for 16 h. Thereaction was partitioned between water and EtOAc, the aqueous layer wasextracted with further EtOAc and the combined organics washed withbrine, dried using a hydrophobic frit and concentrated to a brown gum.This gum was purified by chromatography on silica gel eluting with 0-50%EtOAc:cyclohexane to the product (104 mg, 67%) as a yellow solid. LCMS(2 min Formic): Rt=0.99 min, [MH]⁺=517.

Intermediate 83:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a microwave vial morpholine (0.229 mL, 2.62 mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(fora preparation see Intermediate 13, 1 g, 2.186 mmol), Pd₂(dba)₃(0.100 g, 0.109 mmol), sodium tert-butoxide (0.420 g, 4.37 mmol) andDavePhos (0.1 g, 0.254 mmol) were added in 1,4-dioxane (18 mL). Thevessel was sealed and heated to 100° C. in a microwave reactor for 30min. The mixture was filtered through celite and the filtrate wasconcentrated in vacuo and purified by chromatography on silica geleluting with 0-5% 2M methanolic ammonia:dichloromethane to give theproduct (244 mg, 0.741 mmol, 33.9%) as a brown gum. LCMS (2 min Formic):Rt=0.54 min, [MH]⁺=330.

Intermediate 84: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

In a microwave vessel rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see intermediate 13, 300 mg, 0.656 mmol), tert-butylpiperazine-1-carboxylate (147 mg, 0.787 mmol) sodium tert-butoxide (126mg, 1.312 mmol), Pd₂(dba)₃ (30.0 mg, 0.033 mmol) and DavePhos (25.8 mg,0.066 mmol) were dissolved in 1,4-dioxane. The reaction was irradiatedin a microwave at 100° C. for 2 h. The reaction mixture was allowed tocool and was then filtered through celite washing through with extra1,4-dioxane. The filtrate was concentrated in vacuo to leave the crudewhich was purified by chromatography on silica gel eluting with 0-5% 2Mmethanolic ammonia:dichloromethane to give the product (110 mg, 39%) asa yellow oil. LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=412.

Intermediate 85: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

In a 2.0-5.0 ml microwave vessel rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 84, 110 mg, 0.257 mmol),bromobenzene (0.032 mL, 0.308 mmol) sodium tert-butoxide (49.3 mg, 0.513mmol), Pd₂(dba)₃ (11.75 mg, 0.013 mmol) and DavePhos (10.10 mg, 0.026mmol) were dissolved in 1,4-dioxane. The reaction was irradiated in amicrowave at 100° C. for 2 h. The reaction mixture was allowed to cooland was then filtered through celite washing through with extra1,4-dioxane. The filtrate was concentrated in vacuo to leave the crudewhich was purified using chromatography on silica gel eluting with 0-5%2M methanolic ammonia in dichloromethane to give the product (43 mg,33%) as a yellow oil. LCMS (2 min Formic): Rt=1.32 min, [MH]⁺=505.

Intermediate 86: rac-benzyl((2S,3S,4R)-2-cyclopropyl-3-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The 4-bromoaniline (750 mg, 4.36 mmol) was taken up in DCM (8 mL) andwas treated with cyclopropanecarbaldehyde (0.071 mL, 0.951 mmol) andallowed to stir at rt for 1 h. The reaction was then cooled to 0° C. andwas treated with a solution of (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 190 mg, 0.996 mmol) in DCM (2 mL)followed by diphenyl phosphate (109 mg, 0.436 mmol), the reaction wasallowed to warm to rt and to stir at rt for 16 h. The reaction wasconcentrated to a orange solid and was purified by chromatography onsilica gel eluting with 0-50% EtOAc:cyclohexane to give the product (198mg, 50%) as a buff gum.

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=437.

Intermediate 87: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The rac-benzyl((2S,3S,4R)-2-cyclopropyl-3-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 86, 198 mg, 0.454 mmol) was taken upin dichloromethane (DCM) (10 mL) and treated with DIPEA (0.158 mL, 0.907mmol) and acetyl chloride (0.097 mL, 1.361 mmol) and allowed to stir atrt for 3 days. The reaction was concentrated and purified bychromatography on silica gel eluting with 0-50% EtOAc:cyclohexane togive the product (148 mg, 68%) as a pale yellow gum.

LCMS (2 min Formic): Rt=1.80 min, [MH]⁺=479.

Intermediate 88:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 87, 148 mg, 0.339 mmol) was taken upin ethanol (5 mL) and the reaction was hydrogenated using the H-cube(settings: 25° C., 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart 30 asthe catalyst. The reaction was concentrated and dried to give theproduct (78 mg, 67%) as a colourless gum.

LCMS (2 min Formic): Rt=0.58 min, [MH]⁺=345.

Intermediate 89: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A mixture of (1-ethyl-1H-pyrazol-4-yl)boronic acid (54.7 mg, 0.391mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see intermediate 13, 149 mg, 0.326 mmol), Pd₂(dba)₃(14.92 mg, 0.016 mmol), potassium phosphate (144 mg, 0.678 mmol), andXPhos (15.4 mg, 0.032 mmol) in 1-butanol (2 mL) was heated with stirringin a sealed vial in a microwave reactor for 30 min at 130° C. Themixture was filtered with a celite cartridge and washed with ethylacetate. the solution was evaporated under a stream of nitrogen. Theyellow/brown gum residue was purified by MDAP (HpH) to give the product(58.1 mg, 0.123 mmol, 37.7%) as a pale grey glass.

LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=473.

Intermediate 90:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A stirred mixture of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 89, 58 mg, 0.123 mmol) andpalladium, 10 wt. % (dry basis) on activated carbon, wet, Degussa typeE101 NE/W (12.2 mg, 0.115 mmol) in ethanol (5 mL) was hydrogenated withvigorous stirring under one atmosphere of hydrogen at rt for 2.5 h. Thereaction mixture was filtered over celite, concentrated and dried togive the product (39 mg, 94%).

LCMS (2 min Formic): Rt=0.60 min, [M]⁺=322 (loss of NH₂ ⁻).

Intermediate 91: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A mixture of (1-methyl-1H-pyrazol-4-yl)boronic acid (49.1 mg, 0.390mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see intermediate 13, 148.6 mg, 0.325 mmol), Pd₂(dba)₃(15.8 mg, 0.017 mmol), potassium phosphate (67 mg, 0.316 mmol), andX-Phos (156.4 mg, 0.328 mmol) in 1-butanol (2 mL) was heated withstirring in a sealed vial in a microwave reactor for 1 h at 100° C. Themixture was filtered through a celite cartridge and washed with ethylacetate. The filtrate was concentrated and purified by MDAP (HpH) togive the product (58 mg, 0.126 mmol, 38.9%).

LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=459.

Intermediate 92:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A stirred mixture of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 91, 58 mg, 0.126 mmol) andpalladium, 10 wt. % (dry basis) on activated carbon, wet, Degussa typeE101 NE/W (12.4 mg, 0.117 mmol) in ethanol (5 mL) was hydrogenated withvigorous stirring under one atmosphere of hydrogen at rt for 3 h. Thereaction mixture was filtered over celite, the filtrate was concentratedto give the product (39 mg, 97%) as a grey gum.

LCMS (2 min Formic): Rt=0.56 min, [MH]⁺=308 (loss of NH₂ ⁻).

Intermediate 93:rac-4-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoicacid

A mixture of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see intermediate 13, 159.8 mg, 0.349 mmol),4-boronobenzoic acid (98.4 mg, 0.593 mmol), potassium phosphate (154.3mg, 0.727 mmol), X-Phos (16.0 mg, 0.034 mmol) and Pd₂(dba)₃ (15.6 mg,0.017 mmol) in 1-butanol (2 mL) was irradiated in a microwave at 100° C.for 30 min and then at 120° C. for 30 min. The mixture was allowed tocool to rt and was filtered through a 2.5 g celite cartridge, washingwith ethyl acetate. The combined filtrate was concentrated and purifiedby MDAP (Formic) to give the product (55.8 mg, 0.112 mmol, 32.0%) as awhite solid. LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=499.

Intermediate 94:rac-4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoicacid

A stirred mixture ofrac-4-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoicacid (for a preparation see Intermediate 93, 55.8 mg, 0.112 mmol) andpalladium, 10 wt. % (dry basis) on activated carbon, wet, Degussa typeE101 NE/W (17.1 mg, 0.161 mmol) in ethanol (5 mL) was hydrogenated withvigorous stirring under one atmosphere of hydrogen at rt for 3.5 h. Themixture was filtered under nitrogen through a 2.5 g celite cartridge andthe filter cake washed with ethanol. The combined filtrate wasevaporated in vacuo and dried to give the desired product (28.4 mg,0.078 mmol, 69.6%) as a cream solid.

LCMS (2 min Formic): Rt=0.63 min, [M]⁺=348 (loss of NH₂ ⁻).

Intermediate 95: rac-benzyl((2S,3S,4R)-2,3-dimethyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate

Under nitrogen atmosphere, to a solution of acetaldehyde (0.056 mL, 0.99mmol) in chloroform (5 mL) was added pyridin-3-amine (93 mg, 0.990mmol). The reaction was stirred at rt for 30 min and then cooled to 0°C. Solutions of diphenyl hydrogen phosphate (24.77 mg, 0.099 mmol) inchloroform (2.5 mL) and (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 207 mg, 1.082 mmol) in chloroform (2.5mL) were added. The reaction mixture was stirred at 0° C. for 2 h thenit was heated at 60° C. and stirred for 3 h. Acetaldehyde (0.056 mL,0.99 mmol) and pyridin-3-amine (93 mg, 0.990 mmol) were then added andthe reaction mixture was stirred at 60° C. over the weekend.Acetaldehyde (0.056 mL, 0.99 mmol) was then added and the reactionmixture was stirred at 60° C. for 4 h. The reaction mixture wasevaporated under vacuum and the residue was loaded onto a 25 g silicacartridge and purified by column chromatography using a gradient 0-100%of ethyl acetate in cyclohexane. Desired fractions were combined andevaporated in vacuo to afford the product as a yellow solid (115.6 mg).LCMS (2 min Formic): Rt=0.71 min, [MH]⁺=312.

Intermediate 96: rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate

rac-Benzyl((2S,3S,4R)-2,3-dimethyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 95, 149.7 mg, 0.481 mmol) was takenup in dry DCM (5 mL) under nitrogen at rt. Pyridine (0.117 mL, 1.442mmol) then acetyl chloride (0.051 mL, 0.721 mmol) was added and thereaction mixture was stirred for 2 h at rt. Acetyl chloride (1.5 eq) wasadded and the reaction mixture was stirred at rt for 1 h. The reactionmixture was partitioned between ethyl acetate (30 mL) and saturatedsodium bicarbonate (15 mL). The organic layer was extracted and washedwith water (20 mL) and brine (20 mL) and then dried over a hydrophobicfrit, filtered and concentrated under vacuum. The crude product wastaken up in the minimum of DCM and applied to a 25 g silica cartridgeand eluted with a gradient 0-100% of ethyl acetate in cyclohexane.Desired fractions were combined and evaporated in vacuo to afford theproduct as a colourless solid (141.5 mg). LCMS (2 min Formic): Rt=0.90min, [MH]⁺=354.

Intermediate 97:rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

rac-Benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 96, 141.5 mg, 0.400 mmol) wasdissolved in MeOH (7 mL) and was then passed through a 10% Pd/Ccartridge on a H-cube (rt, full H₂ mode) to give a colourless filtrate.This filtrate was concentrated in vacuo to afford the product as a whitesolid (79 mg).

LCMS (2 min Formic): Rt=0.34 min, [MH]⁺=220.

Intermediate 98: rac-benzyl((2S,3S,4R)-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate

To a solution of cyclopropanecarbaldehyde (1.2 mL, 16.06 mmol) inanhydrous DCM (20 mL) was added 6-methoxypyridin-3-amine (1.59 g, 12.81mmol). The suspension was stirred at rt under nitrogen for 1 h thencooled to 0° C. To the solution was added diphenyl hydrogen phosphate(0.42 g, 1.679 mmol) in anhydrous DCM (5 mL) followed by (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 2.48 g,12.97 mmol) in anhydrous DCM (5 mL). The reaction mixture was stirred at0° C. for 1 h then allowed to warm to rt over 16 h. The reaction mixturewas washed with sat. aq. NaHCO₃ (25 mL) followed by water (25 mL). Theorganic layer was dried through a hydrophobic frit and the solvent wasremoved by rotary evaporation to give the product as a pink solid (3.89g, 10.59 mmol, 83%). LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=368.

Intermediate 99: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate

To a stirred solution of rac-benzyl((2S,3S,4R)-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 98, 3.88 g, 10.56 mmol) in DCM (40mL) and pyridine (2.56 ml, 31.7 mmol) under nitrogen at 0° C. was addedacetyl chloride (1.130 ml, 15.84 mmol). The mixture was stirred at 0° C.for 10 min then allowed to warm to rt over 1 h. The reaction mixture wasdiluted with DCM (40 mL) then washed with 0.5M HCl (50 mL) and saturatedNaHCO₃ (50 mL) and water (50 mL). The organic layer was dried through ahydrophobic frit and concentrated under vacuum to give the product(4.5882 g).

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=410.

Intermediate 100:rac-1-((2S,3R,4R)-4-Amino-2-cyclopropyl-6-methoxy-3-methyl-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

10% Pd/C (11.20 mmol) was added to a solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 99, 4.5882 g, 11.20 mmol) in ethylacetate (100 mL). The reaction was left to stir under an H₂ atmospherefor 72 h then filtered through celite, washed with ethyl acetate andconcentrated in vacuo to give the product (2.8506 g, 10.35 mmol, 92%).

LCMS (2 min Formic): Rt=0.47 min, [MH]⁺=276.

Intermediate 101:rac-1-((2S,3R,4R)-2-cyclopropyl-6-methoxy-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-methoxy-3-methyl-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 100, 1.3421 g, 4.87 mmol),bromobenzene (0.521 ml, 4.95 mmol), sodium tert-butoxide (0.703 g, 7.31mmol), Pd₂(dba)₃ (0.223 g, 0.244 mmol) and DavePhos (0.194 g, 0.492mmol) in anhydrous 1,4-dioxane (12 mL) was stirred and heated undernitrogen to 100° C. for 1 h. The mixture was filtered through celite andwashed with ethyl acetate. The filtrate was then concentrated in vacuoto give a brown gum. The crude was dissolved in DCM, loaded onto a 100 gsilica cartridge and purified over a gradient of 0-75% cyclohexane/ethylacetate. The appropriate fractions were combined and concentrated invacuo to give the product (1.2842 g, 3.65 mmol, 75%) as a yellow gum.

LCMS (2 min Formic): Rt=1.21 min, [MH]⁺=352.

Intermediate 102:rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate

A mixture ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one(for a preparation see Example 101, 1086 mg, 3.22 mmol),2-(N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (1517 mg,3.86 mmol), NEt₃ (0.897 mL, 6.44 mmol) and DMAP (39.3 mg, 0.322 mmol)was stirred at rt in a closed vessel for 72 h. The reaction mixture wasdiluted with DCM (25 mL) and washed with 0.5 M HCl (50 mL) and water (50mL) then dried through a hydrophobic frit. The solvent was evaporated invacuo to leave a brown solid (1.4607 g). The crude was dissolved in DCMand purified on 100 g silica cartridge with a gradient of 0-2.6%DCM/MeOH over 10 CVs. The appropriate fractions were combined andconcentrated in vacuo to give the product (1.078 g, 2.296 mmol, 71%) asa yellow gum.

LCMS (2 min Formic): Rt=1.31 min, [MH]⁺=470.

Intermediate 103: tert-butyl4-((rac-6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-2-methylpiperazine-1-carboxylate

A mixture of tert-butyl 2-methylpiperazine-1-carboxylate (0.077 mL,0.383 mmol),rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 90mg, 0.192 mmol) and cesium carbonate (187 mg, 0.575 mmol) in 1,4-dioxane(7 mL) had nitrogen bubbled through it for 10 min. BINAP (23.87 mg,0.038 mmol) and Pd₂(dba)₃ (17.55 mg, 0.019 mmol) were added and thereaction mixture was stirred at 90° C. under nitrogen for 3 h. Thereaction mixture was allowed to cool to rt then filtered through celite,rinsed with ethyl acetate and concentrated under a stream of nitrogen.The sample was dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified by MDAP(HpH). The appropriate fractions were combined and concentrated invacuo. The sample was dissolved in DMSO:MeOH (1:1, 1 mL) and purified byMDAP (Formic). The appropriate fractions were combined and concentratedin vacuo to give the product (11 mg, 0.021 mmol, 11.04%) as a yellowgum. This was a racemic mixture of diastereoisomers. LCMS (2 minFormic): Rt=1.40 min, [MH]⁺=520.

Intermediate 104: rac-tert-butyl4-((6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)piperazine-1-carboxylate

A mixture ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 30mg, 0.064 mmol), Cs₂CO₃ (62.5 mg, 0.192 mmol) and 1-Boc-piperazine(23.80 mg, 0.128 mmol) in toluene (5 mL) had nitrogen bubbled through itfor 10 min. To this solution was added BINAP (7.96 mg, 0.013 mmol) andPd₂(dba)₃ (5.85 mg, 6.39 μmol) and the mixture was stirred at 90° C. for3 h under nitrogen. The reaction mixture was allowed to cool thenfiltered through celite, rinsed with ethyl acetate and concentratedunder a stream of nitrogen. The sample was dissolved in 1:1 MeOH:DMSO 1mL and purified by MDAP (Formic). The appropriate fractions werecombined and concentrated in vacuo. The sample was dissolved in aminimal amount of MeOH and applied to a 1 g NH₂ column which had beenpre-equilibriated with MeOH (5 mL). The column was flushed with MeOH (5mL) and the appropriate fraction was concentrated in vacuo to give theproduct (17 mg, 0.034 mmol, 52.6%) as a brown/yellow gum. LCMS (2 minHpH): Rt=1.42 min, [MH]⁺=506.

Intermediate 105: rac-tert-butyl(1-((6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)piperidin-4-yl)carbamate

A solution of tert-butyl piperidin-4-ylcarbamate (66.5 mg, 0.332 mmol),rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 78mg, 0.166 mmol) and cesium carbonate (162 mg, 0.498 mmol) in toluene (7mL) had nitrogen bubbled through it for 10 min. Pd₂(dba)₃ (15.21 mg,0.017 mmol) and BINAP (20.69 mg, 0.033 mmol) were then added to themixture which was stirred at 90° C. for 3 h under nitrogen. The reactionmixture was filtered through celite, rinsed with ethyl acetate andconcentrated under a stream of nitrogen to give a brown gum. The samplewas dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified by MDAP (Formic).The appropriate fractions were combined and concentrated in vacuo. Thesample was dissolved in DMSO:MeOH (1:1, 1 mL) and purified by 2×MDAP(Formic). The appropriate fractions were combined and concentrated invacuo to give the product (12 mg, 0.023 mmol, 14%).

LCMS (2 min Formic): Rt=1.18 min, [MH]⁺=520.

Intermediate 106: rac-benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate

To a solution of cyclopropanecarbaldehyde (1.296 mL, 17.34 mmol) inanhydrous DCM (17.5 mL) was added 6-bromopyridin-3-amine (3 g, 17.34mmol) and stirred at rt in a closed vessel for 1 h. A solution ofdiphenyl hydrogen phosphate (0.429 g, 1.717 mmol) in anhydrous DCM (8.75mL) was added, followed by a solution of (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 3.32 g,17.34 mmol) in anhydrous DCM (8.75 ml). The mixture was stirred at rt ina closed vessel for 18 h. The reaction mixture was diluted with DCM (30mL) then washed with sat. NaHCO₃ (aq) (30 mL) then water (30 mL). Theorganic layer was dried over a hydrophobic frit and the solvent wasevaporated under vacuum. The sample was loaded in DCM and purified onsilica (330 g) using 0-10% (MeOH/NH₃)/DCM over 12 CVs. The fractionscontaining product were combined and concentrated in vacuo to give theproduct (1.9804 g, 4.76 mmol, 27%).

LCMS (2 min Formic): Rt=1.21 min, [MH]⁺=416, 418.

Intermediate 107: rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate

To a cooled, stirred solution of rac-benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 106, 1.9804 g, 4.76 mmol) in DCM (25mL) and pyridine (0.577 mL, 7.14 mmol) was added acetyl chloride (0.424mL, 5.95 mmol). The reaction mixture was stirred at rt for 1 h undernitrogen. Further pyridine (0.577 mL, 7.14 mmol) and acetyl chloride(0.424 mL, 5.95 mmol) were added and the reaction mixture was left tostir for an hour under nitrogen. Acetyl chloride (4 mL) and DMAP (0.581g, 4.76 mmol) were added and the reaction mixture was left to stir for22 h at rt under nitrogen. The sample was loaded in DCM and purified onsilica (330 g) using 0-75% ethyl acetate/cyclohexane over 12 CVs. Thefractions were combined and concentrated in vacuo to give the product(596 mg, 27%).

LCMS (2 min Formic): Rt=1.15 min, [MH]⁺=458, 460.

Intermediate 108: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-morpholino-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate

A mixture of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 107, 596 mg, 1.300 mmol), morpholine(0.136 ml, 1.560 mmol), Pd₂dba₃ (59.5 mg, 0.065 mmol), sodiumtert-butoxide (250 mg, 2.60 mmol) and DavePhos (51.2 mg, 0.130 mmol) in1,4-dioxane (12 mL) was stirred at 100° C. for 1 h. The reaction mixturewas filtered through celite and the filtrate was concentrated in vacuo.The crude was taken up in DCM and purified on a 100 g silica cartridgeover a gradient of 0-7.5% DCM/MeOH over 12 CVs. The appropriatefractions were combined and evaporated in vacuo to give a yellow gum.The sample was dissolved in 1:1 MeOH:DMSO (3×1 mL) and purified by MDAP(Formic). The appropriate fractions were combined and the solvent wasevaporated in vacuo to give the product (98.4 mg). LCMS (2 min Formic):Rt=1.08 min, [MH]⁺=465.

Intermediate 109:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

rac-Benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-morpholino-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 108, 96.4 mg, 0.208 mmol) in MeOH (4mL) was hydrogenated using the H-cube (settings: rt, full H₂ mode, 1mL/min flow rate) and 10% Pd/C as a catalyst. The solvent was evaporatedin vacuo to give the product (62.3 mg, 0.189 mmol, 91%) as a clear gum.LCMS (2 min High pH): Rt=0.76 min, [MH]⁺=331.

Intermediate 110:rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate

A solution ofrac-1-((2S,3R,4R)-2-cyclopropyl-6-hydroxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(for a preparation see Example 112, 400 mg, 1.135 mmol), NEt₃ (0.316 mL,2.270 mmol), DMAP (13.87 mg, 0.113 mmol) and2-(N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (535 mg,1.362 mmol) in DCM (10 mL) was stirred at rt in a closed vessel for 1 h.The reaction mixture was diluted with DCM (10 mL) then washed with 0.5 MHCl (20 mL) and water (20 mL). The DCM layer was dried through ahydrophobic frit then concentrated in vacuo. The crude was dissolved inDCM and applied to a 100 g silica cartridge and purified over a gradientof 0-20% DCM/MeOH over 10 CVs. The fractions containing product werecombined and concentrated in vacuo. The sample was dissolved in 1:1MeOH:DMSO (2×3 mL) and purified by MDAP (HpH). The appropriate fractionswere combined and concentrated in vacuo to give the product (440 mg,0.908 mmol, 80%).

LCMS (2 min Formic): Rt=0.78 min, [MH]⁺=485.

Intermediate 111: rac-benzyl((2S,3S,4R)-2,3-dimethyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate

Under nitrogen atmosphere, to a solution of acetaldehyde (0.134 mL, 2.38mmol) in chloroform (10 mL) was added 3-aminopyridin-2(1H)-one (262 mg,2.380 mmol). The reaction was stirred at rt for 1 h and then cooled to0° C. Solutions of diphenyl hydrogen phosphate (59.5 mg, 0.238 mmol) inchloroform (7.5 mL) and (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 501 mg, 2.62 mmol) in chloroform (7.5mL) were added. The reaction was stirred at 0° C. for 2 h. Acetaldehyde(0.134 mL, 2.38 mmol) was then added and the reaction mixture wasstirred at 60° C. for 1 h. Acetaldehyde (0.134 mL, 2.38 mmol) was thenadded and the reaction mixture was stirred at 60° C. overnight. Thesolvent was then evaporated in vacuo, the residue was loaded onto a 100g silica cartridge and purified by column chromatography using agradient 0-20% of 2 M ammonia/MeOH in DCM. Desired fractions werecombined and evaporated in vacuo to afford the product as a white solid(224 mg). LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=328.

Intermediate 112: rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate

rac-Benzyl((2S,3S,4R)-2,3-dimethyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 111, 196 mg, 0.599 mmol) was takenup in dry DCM (7 mL) under nitrogen at rt. Pyridine (0.145 mL, 1.796mmol) then acetyl chloride (0.064 mL, 0.898 mmol) were added and thereaction mixture was stirred for 3 h at rt. Acetyl chloride (0.5 eq) wasadded and the reaction mixture was stirred at rt for 1 h. The reactionmixture was partitioned between ethyl acetate (40 mL) and saturatedsodium bicarbonate (20 mL). The organic layer was extracted and washedwith water (30 mL) and brine (30 mL) and then dried over a hydrophobicfrit, filtered and concentrated under vacuum to afford a green residue.The residue was then dissolved in water, with a small amount of MeOH tohelp the dissolution. Potassium carbonate (83 mg, 0.599 mmol) was thenadded and the solution was stirred at rt for 1 h. The aqueous layer wasthen extracted two times with ethyl acetate, the combined organic layerswere dried over a hydrophobic frit and evaporated in vacuo to afford agreen residue. The crude product was taken up in the minimum of DCM andapplied to a 25 g silica cartridge and eluted with a gradient 0-10% ofMeOH in DCM. Desired fractions were combined and evaporated in vacuo toafford the product as a colourless solid (128.2 mg). LCMS (2 minFormic): Rt=0.74 min, [MH]⁺=370.

Intermediate 113:rac-(2S,3R,4R)-1-Acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate

To a solution of rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 112, 128.2 mg, 0.347 mmol) inpyridine (4 mL) at 0° C. was rapidly added trifluoromethanesulfonicanhydride (0.076 mL, 0.451 mmol). The solution was stirred at 0° C. for2 h. Trifluoromethanesulfonic anhydride (0.030 mL) was added and thereaction mixture was stirred at 0° C. for 1 h. The solution was thenpoured into a separation funnel containing water (25 mL). The mixturewas extracted with DCM (3×20 mL), the combined organic layers were driedover a hydrophobic frit and concentrated under vacuum to afford anorange oil. This oil was loaded onto a 25 g silica cartridge andpurified by column chromatography using a gradient 0-50% of ethylacetate in cyclohexane. Desired fractions were combined and evaporatedin vacuo to afford the product as an orange solid (154.3 mg).

LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=502.

Intermediate 114:rac-1-((2S,3R,4R)-4-Amino-2,3-dimethyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

rac-(2S,3R,4R)-1-Acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate (for a preparation see Intermediate 113, 154.3mg, 0.308 mmol) was dissolved in MeOH (6 mL) and was then passed througha 10% Pd/C cartridge on a H-cube (50° C., full H₂ mode) to give acolourless filtrate. This filtrate was concentrated in vacuo to affordthe product as a colourless solid (108.5 mg).

LCMS (2 min High pH): Rt=0.49 min, [MH]⁺=220.

Intermediate 115: rac-benzyl((2S,3S,4R)-2-cyclopropyl-3-methyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate

Under nitrogen atmosphere, to a solution of cyclopropanecarbaldehyde(0.221 mL, 2.48 mmol) in dry DCM (12 mL) was added3-aminopyridin-2(1H)-one (282 mg, 2.480 mmol). The reaction was stirredat rt for 1 h and then cooled to 0° C. Solutions of diphenyl hydrogenphosphate (62.0 mg, 0.248 mmol) in dry DCM (6 mL) and (E)-benzylprop-1-en-1-ylcarbamate (fora preparation see Intermediate 1, 520 mg,2.72 mmol) in dry DCM (6 mL) were added. The reaction was stirred at 0°C. for 2 h and stirred overnight at rt. Cyclopropanecarbaldehyde (0.221mL, 2.48 mmol) was added and the reaction mixture was stirred at rt for1 h. The reaction mixture was heated at 40° C. and stirred overnight.Cyclopropanecarbaldehyde (0.221 mL, 2.48 mmol) was then added and thereaction mixture was stirred at 40° C. for 3 h. Cyclopropanecarbaldehyde(0.221 mL, 2.48 mmol) and 3-aminopyridin-2(1H)-one (282 mg, 2.480 mmol)were then added and the reaction mixture was stirred at 40° C. for 1.5h. Cyclopropanecarbaldehyde (0.221 mL, 2.48 mmol) was then added and thereaction mixture was stirred at 40° C. for 2.5 h.Cyclopropanecarbaldehyde (0.221 mL, 2.48 mmol) was then added and thereaction mixture was allowed to stand at rt overnight. The solvent wasevaporated in vacuo, the residue was loaded onto a 100 g silicacartridge and purified by column chromatography using a gradient 0-10%of (2M ammonia in MeOH) in DCM. Desired fractions were combined andevaporated in vacuo to afford the product as a white/green solid (238.4mg).

LCMS (2 min Formic): Rt=0.94 min, [MH]⁺=354.

Intermediate 116: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate

rac-Benzyl((2S,3S,4R)-2-cyclopropyl-3-methyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 115, 238.4 mg, 0.675 mmol) was takenup in dry DCM (7 mL) under nitrogen at rt. Pyridine (0.177 mL, 2.188mmol) then acetyl chloride (0.058 mL, 0.809 mmol) were added and thereaction mixture was stirred for 2 h at rt. Acetyl chloride (0.5 eq) wasadded and the reaction mixture was stirred at rt for 1.5 h. Acetylchloride (0.5 eq) was added and the reaction mixture was stirred at rtfor 40 min. Acetyl chloride (0.5 eq) was added and the reaction mixturewas stirred at rt for 1 h. The reaction mixture was partitioned betweenethyl acetate (40 mL) and saturated sodium bicarbonate (20 mL). Theorganic layer was extracted and washed with water (30 mL) and brine (30mL) and then dried over a hydrophobic frit and concentrated undervacuum. The residue was then dissolved in water (20 mL), with a smallamount of MeOH to help the dissolution. Potassium carbonate (93 mg,0.675 mmol) was then added and the solution was stirred at rt for 3 h.The aqueous layer was then extracted with ethyl acetate (3×30 mL), thecombined organic layers were dried over a hydrophobic frit andevaporated in vacuo. The crude product was taken up in the minimumamount of DCM and applied to a 25 g silica cartridge and eluted with agradient 0-10% of MeOH in DCM. Desired fractions were combined andevaporated in vacuo to afford the product as a colourless solid (140mg). LCMS (2 min Formic): Rt=0.80 min, [MH]⁺=396.

Intermediate 117:rac-(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate

To a solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-8-oxo-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 116, 140 mg, 0.354 mmol) in pyridine(4 mL) at 0° C. was rapidly added trifluoromethanesulfonic anhydride(0.078 mL, 0.460 mmol). The solution was stirred at 0° C. for 75 min.Trifluoromethanesulfonic anhydride (0.078 mL, 0.460 mmol) was added andthe reaction mixture was stirred at 0° C. for 2 h. The solution was thenpoured into a separation funnel containing water (25 mL). The mixturewas extracted with DCM (3×20 mL), the combined organic layers were driedover a hydrophobic frit and concentrated under vacuum to afford anorange oil. This oil was loaded onto a 25 g silica cartridge andpurified by column chromatography using a gradient 0-50% of ethylacetate in cyclohexane. Desired fractions were combined and evaporatedin vacuo to afford the product as a colourless solid (185.7 mg).

LCMS (2 min Formic): Rt=1.22 min, [MH]⁺=528.

Intermediate 118:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

rac-(2S,3R,4R)-1-Acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate (for a preparation see Intermediate 117, 151.7mg, 0.288 mmol) was dissolved in MeOH (6 mL) and was then passed througha 10% Pd/C cartridge on an H-cube (50° C., full H₂ mode) to give acolourless filtrate. This filtrate was concentrated in vacuo to affordthe product as a colourless solid (100.7 mg).

LCMS (2 min HpH): Rt=0.59 min, [MH]⁺ not observed.

Intermediate 119: rac-benzyl((2S,3S,4R)-3-methyl-8-oxo-2-propyl-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate

Under an atmosphere of nitrogen, butyraldehyde (0.39 mL, 4.33 mmol) wasadded to a suspension of 3-aminopyridin-2(1H)-one (400 mg, 3.63 mmol) inanhydrous DCM (10 mL). The mixture was stirred at rt for 1.5 h thencooled to 0° C. To the solution was added diphenyl hydrogen phosphate(90 mg, 0.360 mmol) in anhydrous DCM (5 mL) followed by (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 770 mg,4.03 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0° C. for1 h then allowed to warm to rt with stirring over 21 h. The reactionmixture was washed with 2 M aq. NaOH (10 mL) and the aqueous layer wasextracted with DCM (10 mL). The combined organic layers were washed withwater (15 mL) and then dried through a hydrophobic frit. The solvent wasremoved by rotary evaporation to give an off white residue. The residuewas loaded in CHCl₃ and purified on a 100 g silica cartridge using agradient of 0-15% MeOH in DCM over 14 CVs. The appropriate fractionswere combined and the solvent was removed by rotary evaporation to givethe product as a white solid (691 mg, 1.944 mmol, 53.5%).

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=356.

Intermediate 120: rac-benzyl((2S,3R,4R)-1-acetyl-3-methyl-8-oxo-2-propyl-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate

A solution of rac-benzyl((2S,3S,4R)-3-methyl-8-oxo-2-propyl-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 119, 691 mg, 1.944 mmol) andpyridine (0.47 mL, 5.81 mmol) in anhydrous chloroform (10 mL) wastreated with acetyl chloride (0.16 mL, 2.250 mmol). The mixture wasstirred at rt under an atmosphere of nitrogen. Acetyl chloride (0.5 eq.,80 μL) was added to the reaction mixture after 16 h and after 18 h. Thereaction mixture was left to stir over the weekend. After 3 days DMAP(0.1 eq) was added to the reaction mixture, followed by acetyl chloride(0.5 eq., 80 μL). After 30 h, the reaction mixture was warmed to 60° C.overnight. The temperature was increased to 70° C. After 16 h, acetylchloride (3 eq. 0.48 mL) was added. The reaction mixture was allowed tocool to rt and further pyridine (3 eq. 0.47 mL, 5.81 mmol) and acetylchloride (2 eq. 0.32 mL) were added. After 2 h, further acetyl chloride(2 eq. 0.32 mL) was added. After 5 h, DMAP (0.1 eq, 25 mg) was added tothe mixture. After 6.5 h, the reaction mixture was diluted with DCM (5mL) then washed with 2 M aq. HCl (10 mL) followed by sat. aq. NaHCO₃ (10mL) then water (10 mL). The organic layer was dried through ahydrophobic frit and the residue (672 mg) was loaded in CHCl₃ andpurified on a 100 g silica cartridge using a gradient of 0-15% MeOH inDCM over 12 CVs. The appropriate fractions were combined and the solventwas removed by rotary evaporation to give the product as a colourlessoil which solidified (142 mg, 0.357 mmol, 18%). LCMS (2 min Formic):Rt=0.84 min, [MH]⁺=398.

Intermediate 121:rac-(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-3-methyl-2-propyl-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate

To a solution of rac-benzyl((2S,3R,4R)-1-acetyl-3-methyl-8-oxo-2-propyl-1,2,3,4,7,8-hexahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 120, 140 mg, 0.352 mmol) in pyridine(4 mL) was added triflic anhydride (89 μL, 0.527 mmol). The solution wasstirred at 0° C. for 5 h under an atmosphere of nitrogen. (A further 1eq. of triflic anhydride (89 μL, 0.527 mmol) was added after 1 h and 4h). The reaction mixture was quenched by the addition of water (5 mL)and stirred for 15 min at rt. The mixture was extracted with DCM (3×10mL) and the combined organic layers were dried through a hydrophobicfrit. The solvent was removed by rotary evaporation to give a lightbrown residue which was loaded in DCM and purified on a 25 g silicacartridge using a gradient of 0-50% EtOAc in cyclohexane over 14 CVs.The appropriate fractions were combined and the solvent was removed byrotary evaporation to give the product as a yellow oil (159 mg, 0.300mmol, 85% yield). LCMS (2 min Formic): Rt=1.24 min, [MH]⁺=530.

Intermediate 122:rac-1-((2S,3R,4R)-4-Amino-3-methyl-2-propyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

A solution ofrac-(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-3-methyl-2-propyl-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate (for a preparation see Intermediate 121, 156mg, 0.295 mmol) in MeOH (5 mL) was hydrogenated using the H-cube(settings: 50° C., full H₂ mode, 1 mL/min flow rate) and 10% Pd/CCatCart 30 as the catalyst (4 passes through the H-cube in total). Theeluent was then evaporated in vacuo. The colourless residue wassuspended in DCM and the solvent was removed by rotary evaporation togive the product as a white solid (54 mg, 0.218 mmol, 74%). LCMS (2 minFormic): Rt=0.40 min, [MH]⁺=248.

Intermediate 123:rac-(2S,3S)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-ylacetate

To a flask containingrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 894 mg, 3.66 mmol) in aceticacid (10 mL, 175 mmol) was added a solution of sodium nitrite (808 mg,11.71 mmol) in water (3 mL) drop-wise, with a cold water bath to aidcooling. There was an immediate green-yellow colour change. The reactionwas stirred for 1 h. The reaction mixture was diluted with EtOAc (20 mL)and water (20 mL). The layers were separated and the aqueous layerfurther extracted with EtOAc (2×20 mL). The combined organics were driedand concentrated in vacuo to yield a yellow oil (1.05 g, 3.65 mmol,100%) which also contained 25% free hydroxyl. This product mixture wasnot purified and used crude in the subsequent deprotection. This was aracemic mixture of diastereoisomers.

LCMS (2 min Formic): Rt=1.02 min, [MH]⁺=288.

Intermediates 124a & 124b:rac-1-((2S,3S,4R)-2-cyclopropyl-4-hydroxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(120a) &rac-1-((2S,3S,4S)-2-cyclopropyl-4-hydroxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(120b)

To a flask containingrac-(2S,3S)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-ylacetate (for a preparation see Intermediate 123, 1.05 g, 3.65 mmol) inethanol (14 mL) was added potassium hydroxide (0.267 g, 4.75 mmol) atrt. The reaction was stirred for 1 h. The reaction mixture waspartitioned between water (20 mL) and DCM (20 mL). The layers wereseparated and the aqueous phase washed with further DCM. The combinedorganic suspension was dried (Na₂SO₄) and concentrated in vacuo toafford the crude product as a yellow oil. This was dissolved in DCM andpurified by flash chromatography on a silica cartridge (10 g). It waseluted with 0-60% EtOAc/cyclohexane. The appropriate fractions wereconcentrated in vacuo to yieldrac-1-((2S,3S,4R)-2-cyclopropyl-4-hydroxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (434 mg, 1.769 mmol, 48%) as a yellow oil whichcrystallised on standing.

LCMS (2 min Formic): Rt=0.79 min, [MH]⁺=246.

A second eluting set of fractions were also collected and concentratedin vacuo to affordrac-1-((2S,3S,4S)-2-cyclopropyl-4-hydroxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanoneas a pale yellow oil which crystallised on standing (70 mg, 0.285 mmol,8%).

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=246.

Intermediate 125:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonehydrobromide

A stirred mixture of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 13, 3.996 g, 8.74 mmol) andPalladium, 10 wt. % (dry basis) on activated carbon, wet, Degussa typeE101 NE/W (0.828 g, 7.78 mmol) in ethanol (100 mL) and ethyl acetate (70mL) was hydrogenated with vigorous stirring under one atmosphere ofhydrogen at rt for 3 h. The mixture was filtered under nitrogen througha pad of celite filter aid and the filter cake washed with ethanol (3×50mL). The combined filtrate was evaporated in vacuo and dried to give thedesired product (2.488 g, 7.65 mmol, 88%).

LCMS (2 min Formic): Rt=0.49 min, [M]⁺=228 (loss of NH₂ ⁻).

Intermediate 126:rac-1-((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

The tert-butyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 76 500 mg, 1.181 mmol) was taken upin dichloromethane (DCM) (20 mL) and treated with trifluoroacetic acid(0.455 mL, 5.91 mmol) and allowed to stir at rt for 18 h. The reactionwas treated with further TFA (0.182 mL, 2.362 mmol) and allowed to stirat rt for 90 mins. The reaction was concentrated and eluted through aNH₂ SPE (10 g) with MeOH, the MeOH fraction was concentrated and driedto give the product as a white solid (352 mg).

LCMS (2 min Formic): Rt=0.59 min, [M]⁺=306, 308 (loss of NH₂ ⁻).

Intermediate 127: rac-tert-butyl3-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzylcarbamate

In a test tuberac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14,141 mg, 0.491 mmol) sodiumtert-butoxide (79 mg, 0.819 mmol), Pd₂(dba)₃ (18.74 mg, 0.020 mmol) andDavePhos (16.11 mg, 0.041 mmol) were dissolved in 1,4-dioxane (4 mL).The tube was placed in a greenhouse reactor and heated at 100° C. for 2h. The reaction was incomplete so further tert-butyl3-bromobenzylcarbamate (141 mg, 0.491 mmol), sodium tert-butoxide (79mg, 0.819 mmol), Pd₂(dba)₃ (18.74 mg, 0.020 mmol) and DavePhos (16.11mg, 0.041 mmol) were added and the reaction was heated at 100° C. foranother 1 h. The reaction mixture was cooled and filtered throughcelite. The filtrate was concentrated in vacuo to leave the crude.Purification was undertaken by flash column chromatography. The crudematerial was loaded onto a 25 g silica column and eluted using agraduating solvent system of 0-30% ethyl acetate in cyclohexane.Combination and evaporation of the desired fractions gave the product asyellow oil (165 mg). This was only ˜75% pure but was taken on as was tothe subsequent reaction.

LCMS (2 min Formic): Rt=1.21 min, [MH]⁺=450.

Intermediate 128: rac-methyl4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate

Pd₂(dba)₃ (107 mg, 0.117 mmol), DavePhos (92 mg, 0.233 mmol) and sodiumtert-butoxide (168 mg, 1.750 mmol) were all placed in a 2-5 mL microwavevial. To this was added methyl 4-bromobenzoate (251 mg, 1.166 mmol),followed by a fine suspension ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 142.5 mg, 0.583 mmol) in1,4-dioxane (5 mL). The mixture was heated at 120° C. for 40 min in amicrowave heater. The reaction vessel was resealed and heated in amicrowave heater for a further 20 min at 140° C. The mixture wasfiltered through a 2.5 g celite cartridge, washed through with ethylacetate and concentrated in vacuo to afford a yellow crystalline solid.The crude material was taken up in dichloromethane, loaded onto a 10 gsilica flash column, and eluted in 0%-35% ethyl acetate in cyclohexane.The appropriate fractions were collected and evaporated in vacuo toafford a yellow crystalline solid (51.2 mg).

LCMS (2 min formic): Rt=1.12 min, [M]⁺=228 (loss of NHC₆H₄CO₂Me⁻).

Intermediate 129: (E)-tert-butyl but-2-en-1-ylcarbamate

(E)-but-2-en-1-amine (300 mg, 4.22 mmol) was dissolved indichloromethane (DCM) (7 mL) and cooled to 0° C., triethylamine (0.882mL, 6.33 mmol), followed by Boc-anhydride (1.077 mL, 4.64 mmol) wasadded and the reaction stirred overnight and allowed to slowly warm tort as the ice melted. NH₄Cl solution (20 mL) was added and the layerswere separated. The aqueous phase was further extracted with DCM (2×20mL) and the combined organics were dried (Na₂SO₄) and concentrated invacuo to provide the crude product as a colourless oil. This was takenup in DCM and added to a 25 g SNAP silica cartridge. This was purifiedby flash chromatography, eluting with 0->100% EtOAc/cyclohexane. Theappropriate fractions were collected and concentrated in vacuo to affordthe desired product as a colourless oil (706 mg, 4.12 mmol, 98%).

LCMS (2 min formic): Rt=0.97 min, [MH]⁺ not seen.

Intermediate 130: tert-butyl but-1-en-1-ylcarbamate

The (E)-tert-butyl but-2-en-1-ylcarbamate (for a preparation seeIntermediate 129, 300 mg, 1.752 mmol) was placed in a microwaveable vialalong with tris(triphenylphosphine)rhodium(I)carbonyl hydride (40.2 mg,0.044 mmol) and tetrahydrofuran (THF) (15 mL), N₂ was bubbled throughand the vial sealed and irradiated in a microwave at 80° C. for 2 h. Thereaction was treated with triethylamine (0.012 mL, 0.088 mmol) andcooled to −70° C., the reaction was filtered at this temp and thenconcentrated in vacuo to give a brown oil. This oil was purified using a25 g silica column, eluting with: 0-20% EtOAc:cyclohexane. Two closelyeluting peaks (by TLC visualised with ninhydrin) were collected togetherand concentrated in vacuo to afford a colourless oil (160 mg, 0.934mmol, 53.3%). LCMS no peak/mass ion observed.

Intermediate 131: rac-tert-butyl((2S,3S,4R)-2,3-diethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of aniline (0.085 mL, 0.934 mmol) in anhydrousdichloromethane (DCM) (3 mL) was added propionaldehyde (0.074 mL, 1.028mmol). The mixture was stirred at rt under nitrogen for ˜2 h then cooledto 0° C. (ice bath). To the mixture was added first diphenyl hydrogenphosphate (23.38 mg, 0.093 mmol), followed by tert-butylbut-1-en-1-ylcarbamate (for a preparation see Intermediate 130, 160 mg,0.934 mmol) in dichloromethane (DCM) (0.6 mL). Stirring was continued at0° C. and allowed to warm to rt for 2 h. The reaction was allowed tostir overnight and the reaction was stopped by the addition of aqueousNaHCO₃ solution (10 mL). The layers were separated and the aqueous layerwas further extracted with DCM (2×20 mL). The combined organics weredried (Na₂SO₄) and concentrated in vacuo. The crude product was taken upin DCM and added to a 25 g silica cartridge. This was purified by flashchromatography eluting with 0->10% EtOAc/cyclohexane. The appropriatefractions were collected and concentrated in vacuo to afford the desiredproduct as a colourless oil (66.8 mg, 0.219 mmol, 23.48%). LCMS (2 minFormic): Rt=1.26 min, [MH]⁺=305.

Intermediate 132: rac-tert-butyl((2S,3R,4R)-1-acetyl-2,3-diethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The rac-tert-butyl((2S,3S,4R)-2,3-diethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for apreparation see Intermediate 131, 67 mg, 0.220 mmol) was taken up indichloromethane (DCM) (2 mL) and treated with DIPEA (0.081 mL, 0.462mmol) and acetyl chloride (0.031 mL, 0.440 mmol) and allowed to stir atrt for 2 h. The reaction was concentrated to a gum and purified using a10 g silica column, eluting with 0-35% EtOAc:cyclohexane, one major peakwas eluted, the appropriate fractions were collected and concentrated invacuo to afford the product as a colourless oil (76 mg, 0.219 mmol,100%). LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=347.

Intermediate 133:rac-1-((2S,3R,4R)-4-amino-2,3-diethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

The rac-tert-butyl((2S,3R,4R)-1-acetyl-2,3-diethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 132, 76 mg, 0.219 mmol) was taken upin dichloromethane (DCM) (1 mL), treated with TFA (250 μL, 3.24 mmol)and allowed to stir at rt for 2 h, The reaction was concentrated, takenup in MeOH and added to an SCX cartridge (2.5 g). MeOH (3 CVs) waseluted and the product then eluted in 2M NH₃ in MeOH (3 CV). Thesefractions were concentrated to afford the desired product as acolourless oil 44 mg, 0.179 mmol, 81%).

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=230 (loss of NH₂ ⁻).

Intermediate 134: tert-butyl (2-hydroxyethyl)(methyl)carbamate

2-(Methylamino)ethanol (5.32 ml, 66.6 mmol) was dissolved in drydichloromethane (DCM) (30 ml). Boc₂O (17.00 ml, 73.2 mmol) was addedportion-wise and reaction mixture stirred under N₂ at rt. The reactionmixture was left stirring at rt for a further 2 days. The reactionmixture was diluted with water, the organic layer separated and the aq.layer further extracted with DCM. The combined organic layers were dried(Na₂SO₄) and concentrated to give the product (13.29 g, 76 mmol, 114%)as a colourless oil. LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=176.

Intermediate 135: tert-butylmethyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.964 g,20.43 mmol), DIAD (4.42 mL, 22.47 mmol), triphenylphosphine (5.89 g,22.47 mmol) and tert-butyl (2-hydroxyethyl)(methyl)carbamate (for apreparation see Intermediate 134, 3.58 g, 20.43 mmol) were dissolved inTHE at 0° C. under nitrogen for 48 h. The reaction mixture wasconcentrated and the orange oil triturated with diethyl ether. Theprecipitated solid was removed by filtration and washed with morediethyl ether. The filtrate was concentrated to give 12.45 g of crudethick orange oil. This was purified by chromatography on silica (220 gcartridge, eluting with 0-100% ethyl acetate/cyclohexane over 13 CVs,collecting all fractions). Product fractions were combined to give theproduct (4.29 g, 12.21 mmol, 59.8%) as a yellow oil.

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=352.

Intermediate 136: rac-tert-butyl(2-(4-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate

rac-Benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 13, 542 mg, 1.185 mmol), tert-butylmethyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate(for a preparation see Intermediate 135, 500 mg, 1.422 mmol),PdCl₂(dppf) (130 mg, 0.178 mmol) and potassium carbonate (491 mg, 3.56mmol) in 1,4-dioxane (3 mL) and water (1 mL) was sealed in a microwavevial and heated in a microwave at 120° C. for 30 min. The reactionmixture was heated at 120° C. for a further 20 min. The reaction mixturewas concentrated in vacuo and partitioned between DCM and water. Theorganic layer was separated and aqueous layer further extracted withDCM. The combined organic layers were dried (Na₂SO₄) and concentrated togive 1.23 g of crude brown residue. This was purified by chromatographyon silica (50 g cartridge, eluting with 0-100% ethyl acetate/cyclohexaneover 660 mL) to give the product (408 mg, 0.678 mmol, 57.2%) as a yellowoil.

LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=602.

Intermediate 137: rac-tert-butyl(2-(4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate

rac-tert-Butyl(2-(4-((2R,3S,4S)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate(for a preparation see Intermediate 136, 364 mg, 0.605 mmol) wassuspended in ethanol (4 mL). Ethyl acetate (15 mL) was added althoughreaction mixture remained largely a suspension and ammonium formate (381mg, 6.05 mmol) and 10% Pd/C (50 mg, 0.470 mmol) were added and thereaction mixture heated at reflux for 1 h 40 min. The reaction mixturewas cooled to rt and filtered through a celite cartridge (2.5 g). Thereaction mixture was concentrated and loaded onto a 5 g SCX cartridgeequilibrated with MeOH. This was eluted with MeOH (50 mL) followed by 2MNH₃ in MeOH (50 mL). Ammonia fractions were combined and concentrated togive the product (209 mg, 0.447 mmol, 73.9%) as a brown oil. LCMS (2 minFormic): Rt=0.75 min, [MH]⁺=568.

Intermediate 138: rac-tert-butyl(2-(4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate

4-bromobenzonitrile (37.7 mg, 0.207 mmol), DavePhos (16.29 mg, 0.041mmol), Pd₂(dba)₃ (18.96 mg, 0.021 mmol) and sodium tert-butoxide (29.8mg, 0.311 mmol) were added to a 0.5 mL-2 mL microwave vial. To this wasadded rac-tert-butyl(2-(4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate(for a preparation see Intermediate 137, 48.4 mg, 0.104 mmol) in1,4-dioxane (5 mL). The vessel was sealed and heated in a microwaveheater to 120° C. for 40 min. The vessel was resealed and heated to 120°C. for a further 30 min. A further 0.2 eq of Pd₂(dba)₃ and 0.4 eq ofDavePhos were added, the vessel resealed and the mixture heated at 120°C. for 30 min. The reaction mixture was filtered through a 2.5 g celitecartridge, washed through with ethyl acetate and concentrated in vacuoto afford a dark orange glass. The crude material was taken up indichloromethane, loaded onto a 25 g silica flash column, and eluted in0%-30% ethyl acetate in cyclohexane. The column was re-eluted with 5 CVsof 10% 2M NH₃ in dichloromethane. The eluent was collected andevaporated in vacuo. The samples were dissolved in 1:1 MeOH:DMSO 1 mLand purified by MDAP (Formic). The solvent was evaporated in vacuo togive the required product (11.6 mg).

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=569.

Intermediate 139: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

rac-Benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 13, 500 mg, 1.093 mmol) was taken upin 1,4-dioxane (30 mL):water (10 mL) and treated with1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.367 mL, 2.186 mmol), PdCl₂(dppf) (64.0 mg, 0.087 mmol) and potassiumcarbonate (332 mg, 2.405 mmol). The resulting orange solution wasallowed to stir at 85° C. under N₂ for 2 h, The reaction wasconcentrated to remove dioxane and was partitioned between water andDCM, the aqueous layer was extracted with EtOAc, and the combinedorganics were washed with brine, dried using a hydrophobic frit andconcentrated to a brown oil. This oil was purified using a 25 g silicacolumn, elute 0-50% EtOAc:cyclohexane. Nothing eluted so the column wasrun again with 50-100% EtOAc:cyclohexane, one major peak was eluted, theappropriate fractions were summed and concentrated to give the product(335 mg) as a white solid.

LCMS (2 min formic): Rt=1.03 min, [MH]⁺=503.

Intermediate 140:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-Benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 139, 335 mg, 0.667 mmol) was takenup in ethanol (10 mL) and the reaction was hydrogenated using the H-cube(settings: 25° C., 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart 30 asthe catalyst, running through the H-Cube three times. The reaction wasconcentrated and dried to give the product (207 mg) as a colourless gum.LCMS (2 min formic): Rt=0.60 min, [M]⁺=352 (loss of NH₂ ⁻).

Intermediate 141: rac-benzyl((2S,3S,4R)-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of 4-fluoroaniline (1.004 mL, 10.46 mmol) and acetaldehyde(0.588 mL, 10.46 mmol) in DCM (10 mL) was stirred under nitrogen at rtfor 1 h. Diphenyl hydrogen phosphate (0.262 g, 1.046 mmol) and(E)-benzyl prop-1-en-1-ylcarbamate (fora preparation see Intermediate 1,2 g, 10.46 mmol) were added and the reaction mixture was stirred undernitrogen at rt for 16 h. The reaction was diluted with DCM (10 mL),washed with water (2×20 mL) and dried through a hydrophobic frit. Thecrude material in DCM was applied to a 100 g silica snap cartridge andpurified over a gradient of 0-40% cyclohexane/ethyl acetate over 12 CVs.The appropriate fractions were combined and concentrated in vacuo togive the title compound (1.4 g, 4.26 mmol, 41%).

LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=329.

Intermediate 142: rac-benzyl((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of rac-benzyl((2S,3S,4R)-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 141, 1.4 g, 4.26 mmol) and pyridine(1.034 ml, 12.79 mmol) in DCM (20 mL) stirred under nitrogen at 0° C.was added acetyl chloride (0.455 ml, 6.40 mmol). The reaction mixturewas stirred at 0° C. for 10 min then allowed to warm to rt and stirredfor 1 h. The reaction mixture was washed with water (2×20 mL) and theorganic layer was dried through a hydrophobic frit. The solvent wasevaporated in vacuo to give the title compound (1.5 g, 4.05 mmol, 95%).LCMS (2 min Formic): Rt=1.04 min, [MH]⁺=371.

Intermediate 143:rac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-Benzyl((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 142, 1.5 g, 4.05 mmol) in ethanol(40 mL) was hydrogenated using the H-cube (settings: rt, full H₂ mode, 1mL/min flow rate) and 10% Pd/C as a catalyst. The solvent was evaporatedin vacuo to give the title compound (950 mg, 4.02 mmol, 99%).

LCMS (2 min Formic): Rt=0.41 min, [MH]⁺=237.

Intermediate 144: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of cyclopropanecarbaldehyde (0.222 mL, 2.97 mmol) indichloromethane (DCM) (6 mL) was added 4-fluoroaniline (0.256 mL, 2.70mmol). The reaction mixture was stirred at rt under nitrogen for 30 minbefore a solution of diphenyl hydrogen phosphate (67.5 mg, 0.270 mmol)in dichloromethane (DCM) (2 mL) was added and the mixture cooled to 0°C. (ice bath). A solution of (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 516 mg, 2.70 mmol) in dichloromethane(DCM) (2 mL) was added to the mixture. The reaction mixture was stirredat 0° C. under nitrogen and was allowed to warm to rt during thesubsequent 17 h. The mixture was loaded directly onto a 50 g silica gelcartridge which was eluted with a gradient of 0-30% ethyl acetate incyclohexane. The required fractions were combined and the solventevaporated in vacuo to give the desired product (610 mg, 1.721 mmol,63.7%).

LCMS (2 min Formic): Rt=1.20 min, [MH]⁺=355.

Intermediate 145: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of rac-benzyl((2S,3S,4R)-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 145, 1.173 g, 3.31 mmol) andpyridine (0.803 mL, 9.93 mmol) in Anydrous Dichloromethane (DCM) (20 mL)was treated with acetyl chloride (0.282 mL, 3.97 mmol). The mixture wasstirred at rt under an atmosphere of nitrogen overnight. The reactionmixture was transferred to a separating funnel, diluted with DCM (30 mL)and washed with 1M aq. HCl (50 mL) followed by sat. aq. NaHCO₃ (50 mL)and brine (50 mL). The organic layer was dried through a hydrophobicfrit and the solvent was removed by rotary evaporation to give theproduct as a solid (1.29 g). This was pure enough to use in subsequentsteps.

LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=397.

Intermediate 146:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see intermediate 146, 1.29 g, 3.25 mmol) in ethanol(30 mL) was passed through a Thales H-cube flow hydrogenator with afitted with a 10% Pd/C CatCart at a rate of 1 mL/min in full H₂ mode.After 1 pass the reaction was incomplete so the solution was passedthrough the reactor a second time. The solvent was removed under reducedpressure to leave the product as a pale yellow solid (955 mg).

LCMS (2 min Formic): Rt=0.50 min, [M]⁺=246 (loss of NH₂ ⁻).

Intermediate 147: rac-tert-butyl((2S,3S,4R)-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Under nitrogen, 4-bromoaniline (2 g, 11.63 mmol) and acetaldehyde (0.975mL, 17.44 mmol) were dissolved in DCM (40 mL) and stirred at rt for 1 h.The reaction was then cooled to 0° C. and diphenyl hydrogen phosphate(0.291 g, 1.163 mmol) in DCM (5 mL) and (E)-tert-butylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 74, 2.193 g,13.95 mmol) in DCM (5 mL) were sequentially added. The reaction wasstirred and allowed to warm to rt overnight. The solvent was removedunder reduced pressure to leave the crude. The crude material was loadedonto a 100 g silica column and eluted using a graduating solvent systemof 0-20% EtOAc/cyclohexane. Combination and evaporation of the desiredfractions gave the product as a yellow solid (1.32 g). Slightly lesspure fractions were also combined and evaporated to give a second batchas a yellow solid (322 mg). LCMS (2 min Formic): Rt=1.23 min, [MH]⁺=355,357.

Intermediate 148: rac-tert-butyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

rac-tert-Butyl((2S,3S,4R)-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 148, 1.642 g, 4.62 mmol) was takenup in dichloromethane (DCM) (40 mL) and treated with DIPEA (1.695 mL,9.71 mmol) and acetyl chloride (0.657 mL, 9.24 mmol) and allowed to stirat rt for 2 h. The reaction was concentrated to a gum, taken up in DCMand added to a silica cartridge (100 g) and purified using flashchromatography, eluting with 0-40% EtOAc/cyclohexane, one major peak waseluted, the appropriate fractions were collected and concentrated invacuo to afford the desired product as a yellow solid (1.05 g, 2.64mmol, 57.2%). LCMS (2 min Formic): Rt=1.13 min, [MH]⁺=397.

Intermediate 149: rac-tert-butyl((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(317 mg, 1.510 mmol), rac-tert-butyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 149, 400 mg, 1.01 mmol) and cesiumcarbonate (984 mg, 3.02 mmol) were suspended in 1,4-dioxane (20 mL) andwater (2 mL). The reaction mixture was treated with Pd(PPh₃)₄ (116 mg,0.101 mmol) then stirred at 80° C. for 3 h. The reaction mixture waspartitioned between water and EtOAc, the aqueous layer further extractedwith EtOAc and the combined organic layer were washed with brine, driedover Na₂SO₄ then concentrated in vacuo to a dark oil. The dark oil waspurified by silica chromatography, eluting with a 0 to 80%EtOAc/cyclohexane solvent gradient to give the desired product as ayellow foam (416 mg).

LCMS (2 min Formic): Rt=1.02 min, [MH]⁺=401.

Intermediate 150:rac-1-((2S,3R,4R)-4-amino-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-tert-butyl((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 150, 416 mg, 1.039 mmol) in DCM (10mL) was treated with TFA (5 mL, 64.9 mmol) and the mixture allowed tostand overnight then concentrated under reduced pressure. The resultingbrown residue was dissolved in methanol then passed through a 10 gamino-propyl SPE column which was washed through with further methanol.The combined methanol washes was concentrated under reduced pressure togive the desired product as a pale yellow gum (303 mg, 97%).

LCMS (2 min Formic): Rt=0.55 min, [M]⁺=284 (loss of NH₂ ⁻).

Intermediate 151: rac-benzyl((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

rac-Benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 3, 0.55 g, 1.275 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.402 g, 1.913 mmol) and cesium carbonate (1.246 g, 3.83 mmol) werestirred in 1,4-Dioxane (15 mL) and Water (1.5 mL) and treated withpalladium tetrakis (0.147 g, 0.128 mmol). The reaction was heated underreflux. The reaction was allowed to cool to rt and was partitionedbetween EtOAc (50 mL) and water (50 mL), the organic layer was washedwith brine (50 mL), dried using a hydrophobic frit and concentrated togive the crude product. Purification was undertaken by flash columnchromatography. The crude material was loaded onto a 50 g silica columnand eluted using a graduating solvent system of 0-50% ethyl acetate incyclohexane. The desired fractions were combined and concentrated invacuo to leave the product as a pale yellow solid (450 mg). LCMS (2 minHpH): Rt=1.04 min, [MH]⁺=435.

Intermediate 152:rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 152, 450 mg, 1.036 mmol) in ethanol(10 mL) was passed through a Thales H-cube flow hydrogenator fitted witha 10% Pd/C CatCart at a rate of 1 mL/min in full H₂ mode. The reactionmixture was passed through the reactor twice. Then the solvent wasremoved under reduced pressure to leave the product as a white solid(225 mg). LCMS (2 min Formic): Rt=0.52 min, [M]⁺=286 (loss of NH₂ ⁻).

Intermediate 153: rac-benzyl((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(163 mg, 0.778 mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 9, 231 mg, 0.519 mmol), cesiumcarbonate (507 mg, 1.556 mmol) were suspended in 1,4-dioxane (10 mL) andwater (1 mL) and were treated with Pd(PPh₃)₄ (30.0 mg, 0.026 mmol). Thereaction was allowed to stir at 80° C. under N₂ for 16 h. The reactionsolution was partitioned between ethyl acetate (35 mL) and water (35 mL)and the layers separated, the aqueous layer was washed with ethylacetate (35 mL) and the organic layers combined. The combined organicswere washed with brine (30 mL) and passed through a hydrophobic fritbefore being concentrated in vacuo to give 388 mg of crude yellow oil.This was purified by chromatography on silica (25 g, eluting with 0-55%ethyl acetate/cyclohexane). The fractions containing product werecombined and concentrated in vacuo to give the product (172 mg, 0.383mmol, 73.9%) as a white solid. LCMS (2 min Formic): Rt=1.08 min,[MH]⁺=449.

Intermediate 154:rac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-Benzyl((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 154, 170 mg, 0.379 mmol) was takenup in ethanol (10 mL). The solution was hydrogenated using the H-cube(settings: rt, 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart as thecatalyst. The solution was left to cycle through the H-cube on the samesettings for 40 min. After a further 1.5 h the reaction mixture wasconcentrated in vacuo to give 143 mg of crude product as a yellow solid.The sample was loaded in methanol and purified by SPE on sulphonic acid(SCX) 2 g using a sequential solvents methanol, 2M ammonia/methanol. Theappropriate fractions were combined and evaporated in vacuo to give 113mg of an off white solid. This was purified by chromatography on silica(10 g, eluting with 0-5% methanolic ammonia/DCM). The fractionscontaining product were combined and concentrated in vacuo to give theproduct (114 mg, 0.360 mmol, 95%) as a white solid.

LCMS (2 min Formic): Rt=0.58 min, [MH]⁺=300 (loss of NH₂ ⁻).

Intermediate 155: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see intermediate 3, 1 g, 2.318 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.075 g, 3.48 mmol), cesium carbonate (2.266 g, 6.96 mmol) andPd(PPh₃)₄ (0.268 g, 0.232 mmol) in 1,4-dioxane (30 mL) and water (3 mL)was stirred under nitrogen at 100° C. for 1 h. The reaction mixture wasconcentrated in vacuo and redissolved in DCM (20 mL) which was washedwith water (2×20 mL). The organic layer was dried through a hydrophobicfrit and applied to a 100 g silica column and purified over a gradientof 0-40% ethyl acetate/cyclohexane over 12 CVs. The appropriatefractions were combined and concentrated in vacuo to give the titlecompound (1.12 g, 2.10 mmol, 91%).

LCMS (2 min Formic): Rt=1.24 min, [MH]⁺=534.

Intermediate 156: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 156, 1.1245 g, 2.107 mmol) inethanol (40 mL) was hydrogenated using the H-cube (settings: rt, full H₂mode, 1 mL/min flow rate) and 10% Pd/C as a catalyst. The reactionmixture was concentrated in vacuo and dissolved in ethanol (10 mL) and10% Pd/C (1.1245 g, 10.57 mmol) was added. The reaction was left to stirunder an H₂ atmosphere for 16 h then filtered through celite, washedwith ethyl acetate and concentrated in vacuo to give the title compound(700 mg, 1.743 mmol, 83%).

LCMS (2 min Formic): Rt=0.79 min, [MH]⁺=402.

Intermediate 157: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 157, 60 mg, 0.149 mmol), DavePhos(5.88 mg, 0.015 mmol), 2-bromo-5-methylpyrazine (25.9 mg, 0.149 mmol),Pd₂(dba)₃ (6.84 mg, 7.47 μmol) and sodium tert-butoxide (28.7 mg, 0.299mmol) in 1,4-Dioxane (3 mL) was stirred under nitrogen at 90° C. for 5h. The reaction mixture was allowed to cool to room temp, filteredthrough celite and rinsed with ethyl acetate. The solvent was evaporatedin vacuo and dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified by MDAP(Formic). The appropriate fractions were combined and concentrated invacuo to give the title compound (23 mg, 0.047 mmol, 31%).

LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=494.

Intermediate 158: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 157, 100 mg, 0.249 mmol), DavePhos(9.80 mg, 0.025 mmol), 2-bromo-5-fluoropyridine (43.8 mg, 0.249 mmol),Pd₂(dba)₃ (11.40 mg, 0.012 mmol) and sodium tert-butoxide (47.9 mg,0.498 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C.for 5 h. The reaction mixture was allowed to cool to rt, filteredthrough celite and rinsed with ethyl acetate. The solvent was evaporatedin vacuo and the samples were dissolved in 1:1 MeOH:DMSO (1 mL) andpurified by MDAP (HpH). The appropriate fractions were combined andconcentrated in vacuo to give the title compound (67 mg, 0.135 mmol,54.2%).

LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=497.

Intermediate 159: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 157, 100 mg, 0.249 mmol), DavePhos(9.80 mg, 0.025 mmol), 2-bromo-6-methylpyridine (42.8 mg, 0.249 mmol),Pd₂(dba)₃ (11.40 mg, 0.012 mmol) and sodium tert-butoxide (47.9 mg,0.498 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C.for 5 h. The reaction mixture was allowed to cool to rt, filteredthrough celite and rinsed with ethyl acetate. The solvent was evaporatedin vacuo and dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified by MDAP(Formic). The appropriate fractions were combined and concentrated invacuo to give the title compound (55 mg, 0.112 mmol, 45%).

LCMS (2 min Formic): Rt=0.95 min, [MH]⁺=493.

Intermediate 160: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 157, 50 mg, 0.125 mmol), DavePhos(4.90 mg, 0.012 mmol), 4-bromobenzonitrile (27.2 mg, 0.149 mmol),Pd₂(dba)₃ (5.70 mg, 6.23 μmol) and sodium tert-butoxide (23.93 mg, 0.249mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C. for 5h. The reaction mixture was allowed to cool to rt, filtered throughcelite and rinsed with ethyl acetate. The solvent was evaporated invacuo then dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified by MDAP(Formic). The appropriate fractions were combined and concentrated invacuo to give the product (20 mg, 0.040 mmol, 32.0%). LCMS (2 minFormic): Rt=1.21 min, [MH]⁺=503.

Intermediate 161: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 157, 65 mg, 0.162 mmol),6-fluoronicotinonitrile (39.5 mg, 0.324 mmol), and DIPEA (0.057 mL,0.324 mmol) in N-methyl-2-pyrrolidone (NMP) (1.5 mL) was heated in amicrowave at 200° C. for 30 min. The reaction mixture was purifieddirectly by MDAP (Formic). The appropriate fractions were combined andconcentrated in vacuo to give the product (21 mg, 0.042 mmol, 25.8%yield).

LCMS (2 min Formic): Rt=1.15 min, [MH]⁺=504.

Intermediate 162: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 157, 55 mg, 0.137 mmol), DavePhos(5.39 mg, 0.014 mmol), 4-bromo-N-methylbenzamide (35.2 mg, 0.164 mmol),Pd₂(dba)₃ (6.27 mg, 6.85 μmol) and sodium tert-butoxide (26.3 mg, 0.274mmol) in 1,4-dioxane (2 mL) was stirred under nitrogen at 90° C. for 5h. The reaction mixture was allowed to cool to rt, filtered throughcelite and rinsed with ethyl acetate. The solvent was evaporated invacuo and the sample was dissolved in 1:1 MeOH:DMSO (2×1 mL) andpurified by MDAP (Formic). The appropriate fractions were combined andconcentrated in vacuo to give the product (15 mg, 0.028 mmol, 20.48%).

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=535.

Intermediate 163: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a dried flask under nitrogen was added tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 81, 250 mg, 0.587 mmol),2-bromo-6-methoxypyridine (0.087 mL, 0.705 mmol), DavePhos (88 mg, 0.223mmol), Pd₂(dba)₃ (102 mg, 0.112 mmol) and sodium tert-butoxide (169 mg,1.762 mmol). To this was added 1,4-dioxane (5 mL) and the solution wasdegassed with nitrogen for ˜5 min. The mixture was then heated for 2 hat 90° C. under nitrogen. The mixture was allowed to cool to rt,filtered through a 2.5 g celite cartridge, washed through with ethylacetate and concentrated in vacuo to afford a dark orange oil. The crudeproduct was taken up in DCM and purified on a 25 g silica cartridge byflash chromatography eluting with 0-50% EtOAc/cyclohexane. Theappropriate fractions were collected and concentrated in vacuo to affordthe desired product as an off-white foam (202 mg, 0.379 mmol, 64.6%).LCMS (2 min Formic): Rt=1.33 min, [MH]⁺=533.

Intermediate 164: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a dried flask under nitrogen was added rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 81, 200 mg, 0.470 mmol),4-bromobenzonitrile (103 mg, 0.564 mmol), DavePhos (74.0 mg, 0.188mmol), Pd₂(dba)₃ (86 mg, 0.094 mmol) and sodium tert-butoxide (135 mg,1.410 mmol). To this was added 1,4-dioxane (4 mL), and the solution wasdegassed with nitrogen for ˜5 min. The mixture was then heated for 2 hat 90° C. under nitrogen. Heating was continued overnight. The reactionmixture was allowed to cool to rt, filtered through a 2.5 g celitecartridge, washed through with ethyl acetate and concentrated in vacuoto afford a dark brown oil. The crude product was taken up in DCM andpurified on a 25 g silica cartridge by flash chromatography eluting with0-50% EtOAc/cyclohexane. The appropriate fractions (which contained someminor impurities) were collected and concentrated in vacuo to afford thedesired product as an off-white foam (93.2 mg, 0.177 mmol, 37.7%). LCMS(2 min Formic): Rt=1.27 min, [MH]⁺=527.

Intermediate 165: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

In a test tube rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 81, 200 mg, 0.470 mmol),4-bromo-N-methylbenzamide (121 mg, 0.564 mmol), sodium tert-butoxide (90mg, 0.940 mmol), Pd₂(dba)₃ (21.52 mg, 0.023 mmol) and DavePhos (18.50mg, 0.047 mmol) were dissolved in 1,4-dioxane (4 mL). The solution wasstirred and heated at 100° C. for 2 h. The reaction mixture was allowedto cool and was then filtered through celite washing through with extradioxane. The filtrate was concentrated in vacuo to leave the crude.Purification was undertaken by flash column chromatography. The crudematerial was loaded onto a 25 g silica column and eluted using agraduating solvent system of 0-5% 2M methanolic ammonia indichloromethane. Combination and evaporation of the desired fractionsgave the product as a yellow foam (110 mg). Less pure fractions werealso pooled and concentrated to give product. This was purified usingMDAP (Formic). Evaporation of the desired fractions gave the product asa white solid (10 mg).

LCMS (2 min Formic): Rt=1.13 min, [MH]⁺=559.

Intermediate 166: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

In a test tube rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 81, 200 mg, 0.470 mmol),2-bromo-4-methylpyrimidine (98 mg, 0.564 mmol), sodium tert-butoxide (90mg, 0.940 mmol), Pd₂(dba)₃ (21.52 mg, 0.023 mmol) and DavePhos (18.50mg, 0.047 mmol) were dissolved in 1,4-dioxane (4 mL). The solution wasstirred and heated at 100° C. for 2 h. The reaction mixture was allowedto cool and was then filtered through celite washing through with extradioxane. The filtrate was concentrated in vacuo to leave the crude.Purification was undertaken by flash column chromatography. The crudematerial was loaded onto a 25 g silica column and eluted using agraduating solvent system of 0-5% 2M methanolic ammonia indichloromethane. Combination and evaporation of the desired fractionsgave the product as a yellow oil (10 mg).

LCMS (2 min Formic): Rt=1.18 min, [MH]⁺=518.

Intermediate 167: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 164, 78 mg, 0.15 mmol) was taken upin ethanol (10 mL) and the reaction was hydrogenated using the H-cube(settings: 25° C., 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart 30 asthe catalyst. The sample was allowed to cycle through the H-cube for 30min. The reaction was concentrated in vacuo to give the crude productwhich was used in the following step without further purification.

LCMS (2 min Formic): Rt=1.26 min, [MH]⁺=529.

Intermediate 168: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

tert-Butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 165, 78 mg, 0.140 mmol) was taken upin ethanol (10 mL) and the reaction was hydrogenated using the H-cube(settings: 25° C., 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart 30 asthe catalyst. The sample was allowed to cycle through the H-cube for 30min and the reaction mixture was concentrated in vacuo. The cruderesidue was dissolved in a 1:1 DMSO/MeOH mixture and was purified viaMDAP (Formic). The appropriate fractions were combined and concentratedin vacuo to give the product a viscous colourless oil (35 mg).

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=561.

Intermediate 169: rac-benzyl((2S,3S,4R)-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A stirred solution of (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 1.18 g, 6.17 mmol), 4-morpholinoaniline(1.00 g, 5.61 mmol) and acetaldehyde (0.472 mL, 8.42 mmol) in DCM (45ml) under nitrogen was cooled using an ice/water bath for 15 min then asolution of diphenyl hydrogen phosphate (0.140 g, 0.561 mmol) in DCM (5ml) was added dropwise to the reaction mixture. The reaction mixture wasallowed to warm to rt overnight then washed with sat. NaHCO₃ (aq., 100mL) and the aqueous layer was extracted with DCM (100 mL). The combinedorganic layer was concentrated under reduced pressure then purified bysilica column, eluting with a gradient of 0 to 50% EtOAc in cyclohexane,followed by 50% EtOAc in cyclohexane to give the desired product as awhite solid (1.14 g). LCMS (2 min Formic): Rt=0.81 min, [MH]⁺=396.

Intermediate 170: rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of rac-benzyl((2S,3S,4R)-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 169, 1.1 g, 2.78 mmol) and pyridine(0.675 mL, 8.34 mmol) in anhydrous DCM (15 mL) was treated with acetylchloride (0.475 mL, 6.68 mmol). The mixture was stirred at rt for 16 hthen washed with 1M HCl (aq., 20 mL) followed by saturated NaHCO₃ (aq.,20 mL) and brine (20 mL). The organic layers were concentrated underreduced pressure to give the desired product as a pale brown solid (1.1g, 90%).

LCMS (2 min Formic): Rt=0.95 min, [MH]⁺=438.

Intermediate 171:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 83, 70 mg, 0.212 mmol), DavePhos(8.36 mg, 0.021 mmol), Pd₂(dba)₃ (9.73 mg, 10.62 μmol), sodiumtert-butoxide (0.027 mL, 0.425 mmol) and 2-bromo-6-methoxy-pyridine(47.9 mg, 0.255 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogenat 90° C. for 8 h. The reaction mixture was allowed to cool to rt,filtered through celite and rinsed with ethyl acetate. The solvent wasevaporated in vacuo to give the title compound (120 mg, 0.275 mmol, 92%pure) as a brown gum. LCMS (2 min Formic): Rt=1.03 min, [MH]⁺=437.

Intermediate 172: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

To a flask containing rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 9, 850 mg, 1.909 mmol) was addedtoluene (25 mL) and the flask evacuated and back filled with N₂ (×2). Tothis was added tert-butyl piperazine-1-carboxylate (0.711 mL, 3.82 mmol)and sodium tert-butoxide (367 mg, 3.82 mmol) and the resultantsuspension then had N₂ bubbled through it for ˜5 min. DavePhos (75 mg,0.191 mmol) and Pd₂(dba)₃ (175 mg, 0.191 mmol) were then added and N₂was bubbled through the reaction mixture for a further ˜5 min. Thereaction was then heated to 110° C. for 1.5 h. The reaction mixture wasthen diluted with EtOAc (40 mL) and filtered through celite (10 g). Thecelite was washed with further EtOAc (2×40 mL) and the combined organicsconcentrated in vacuo. The crude product was taken up in DCM and addedto a silica cartridge (100 g). This was purified by flashchromatography, eluting with 0-50% (20% (2M NH₃ in MeOH)/DCM)/DCM. Theappropriate fractions were collected and concentrated in vacuo to affordthe desired product as a brown foam (371 mg, 0.891 mmol, 46.7%). LCMS (2min Formic): Rt=0.78 min, [M]⁺=400 (loss of NH₂ ⁻).

Intermediate 173: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 172, 46 mg, 0.110 mmol) in1,4-dioxane (1.5 mL) was then added. To this was added2-chloro-5-methylpyrazine (28.4 mg, 0.221 mmol), sodium tert-butoxide(21.23 mg, 0.221 mmol) and DavePhos (8.69 mg, 0.022 mmol) and theresultant suspension then had N₂ bubbled through it for ˜5 min.Pd₂(dba)₃ (20.22 mg, 0.022 mmol) was added and N₂ was bubbled throughthe reaction mixture for a further ˜5 min. The reaction was then heatedto 100° C. for 30 min in a microwave. The reaction was then reheated to100° C. in a microwave for 30 min. The reaction mixture was diluted withEtOAc and filtered though celite (2.5 g). The celite was washed withfurther EtOAc (2×10 mL) and the resultant solution concentrated invacuo. This was taken up in MeOH/DMSO (1:1, 0.9 mL) and purified by MDAP(Formic). The appropriate fraction was collected and concentrated invacuo to afford an orange glass (21.6 mg, 0.042 mmol, 38.5%).

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=509.

Intermediate 174: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 172, 46 mg, 0.110 mmol) in1,4-dioxane (1.5 mL) was then added. To this was added4-bromobenzonitrile (40.2 mg, 0.221 mmol), sodium tert-butoxide (21.23mg, 0.221 mmol) and DavePhos (8.69 mg, 0.022 mmol) and the resultantsuspension then had N₂ bubbled through it for ˜5 min. Pd₂(dba)₃ (20.22mg, 0.022 mmol) was added and N₂ was bubbled through the reactionmixture for a further ˜5 min. The reaction was then heated to 100° C.for 30 min in a microwave. The reaction mixture was diluted with EtOAcand filtered though celite (2.5 g). The celite was washed with furtherEtOAc (2×10 mL) and the resultant solution concentrated in vacuo. Thiswas taken up in MeOH/DMSO (1:1, 0.9 mL) and purified by MDAP (Formic).The appropriate fraction was collected and concentrated in vacuo toafford an orange glass (24 mg, 0.046 mmol, 42.0%). LCMS (2 min Formic):Rt=1.19 min, [MH]⁺=518.

Intermediate 175: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 172, 46 mg, 0.110 mmol) in1,4-dioxane (1.5 mL) was then added. To this was added4-bromo-N-methylbenzamide (0.047 mL, 0.221 mmol), sodium tert-butoxide(21.23 mg, 0.221 mmol) and DavePhos (8.69 mg, 0.022 mmol) and theresultant suspension then had N₂ bubbled through it for ˜5 min.Pd₂(dba)₃ (20.22 mg, 0.022 mmol) was added and N₂ was bubbled throughthe reaction mixture for a further ˜5 min. The reaction was then heatedto 100° C. for 30 min in a microwave. The reaction was then reheated to100° C. in a microwave for 30 min. The reaction mixture was diluted withEtOAc and filtered though celite (2.5 g). The celite was washed withfurther EtOAc (2×10 mL) and the resultant solution concentrated invacuo. This was taken up in MeOH/DMSO (1:1, 0.9 mL) and purified by MDAP(Formic). The appropriate fraction was collected and concentrated invacuo to afford an orange glass (13 mg, 0.024 mmol, 21.42%).

LCMS (2 min Formic): Rt=1.04 min, [MH]⁺=550.

Intermediate 176: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 172, 37 mg, 0.089 mmol) inN-methyl-2-pyrrolidone (NMP) (1 mL) was then added. To this was added5-chloropyrazine-2-carbonitrile (24.79 mg, 0.178 mmol), and DIPEA (0.047mL, 0.266 mmol) and the resultant solution then heated to 150° C. for 30min in a microwave. The reaction mixture was filtered through a cottonwool plug directly into two LCMS vials and was then purified by 2×MDAP(Formic). The appropriate fractions were collected and concentrated invacuo to afford the desired product as a brown gum (26.6 mg, 0.051 mmol,57.6%).

LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=520.

Intermediate 177: rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 172, 37 mg, 0.089 mmol) inN-methyl-2-pyrrolidone (NMP) (1 mL) was then added. To this was added6-fluoronicotinonitrile (21.69 mg, 0.178 mmol), and DIPEA (0.047 mL,0.266 mmol) and the resultant solution then heated to 150° C. for 30 minin a microwave. The reaction was then reheated to 150° C. for 30 min.The reaction mixture was filtered through a cotton wool plug directlyinto two LCMS vials and was then purified by 2×MDAP (Formic). Theappropriate fractions were collected and concentrated in vacuo to affordthe desired product as a brown gum (16.6 mg, 0.032 mmol, 36.0%). LCMS (2min Formic): Rt=1.12 min, [MH]⁺=519.

Intermediate 178: (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a dried flask was added (S)-tert-butyl2-methylpiperazine-1-carboxylate (52.3 mg, 0.261 mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(fora preparation see Intermediate 13, 99.5 mg, 0.218 mmol), sodiumtert-butoxide (41.8 mg, 0.435 mmol), Pd₂(dba)₃ (9.96 mg, 10.88 μmol) andDavePhos (8.56 mg, 0.022 mmol) under nitrogen. To this was added1,4-dioxane (2 mL), and the solution was stirred and degassed withnitrogen for ˜15 min. The mixture was heated to 90° C. overnight. Themixture was allowed to cool to rt, filtered through a 2.5 g celitecartridge, washed through with ethyl acetate and concentrated in vacuo.The residue was taken up in dichloromethane, loaded onto a 25 g silicaflash column, and eluted in 10%-50% ethyl acetate in cyclohexane. Theappropriate fractions were collected and concentrated in vacuo to afforda yellow oil (48.4 mg, 0.084 mmol, 38.6%). This was a mixture ofdiastereoisomers. LCMS (2 min formic): Rt=1.29 min, [MH]⁺=577.

Intermediate 179: (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a carousel flask, evacuated and back-filled with nitrogen, was added10% Pd/C (35.7 mg, 0.034 mmol). To this was added a solution of(S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 178, 48.4 mg, 0.084 mmol) in ethanol(3 mL). The flask was allowed to stir under a hydrogen atmosphere for 4h. The reaction mixture was filtered through a 2.5 g celite cartridgewith ethanol, and the eluent collected. The eluted solution wasevaporated in vacuo to afford a pale grey, transparent oil (37.7 mg,0.085 mmol). This was a mixture of diastereoisomers. LCMS (2 minformic): Rt=0.87 min, [MH]⁺=443.

Intermediate 180: (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a flask containing (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 179, 37.7 mg, 0.085 mmol) in1,4-dioxane (2 mL) under nitrogen was added sodium tert-butoxide (24.56mg, 0.256 mmol), 4-bromobenzonitrile (18.60 mg, 0.102 mmol), Pd₂(dba)₃(15.60 mg, 0.017 mmol) and DavePhos (13.41 mg, 0.034 mmol). The mixturewas degassed with nitrogen for ˜15 min, and then heated to 90° C. withstirring under nitrogen for ˜2 h, followed by heating at 45° C. for ˜64h. The mixture was filtered over a 2.5 g celite cartridge, washedthrough with ethyl acetate and concentrated in vacuo. The residue wastaken up in dichloromethane, loaded onto a 10 g silica flash column andeluted by silica gel chromatography in 0%-25% ethyl acetate incyclohexane. The appropriate fractions were collected and concentratedin vacuo to afford a sticky yellow oil (25.4 mg, 0.021 mmol, 24.68%).This was a mixture of diastereoisomers.

LCMS (2 min formic): Rt=1.26 min, [MH]⁺=544.

Intermediate 181: (R)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a dried flask was added (R)-tert-butyl2-methylpiperazine-1-carboxylate (51.6 mg, 0.258 mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(fora preparation see Intermediate 13, 98.2 mg, 0.215 mmol), sodiumtert-butoxide (41.3 mg, 0.429 mmol), Pd₂(dba)₃ (9.83 mg, 10.74 μmol) andDavePhos (8.45 mg, 0.021 mmol) under nitrogen. To this was added1,4-dioxane (2 mL), and the solution was stirred and degassed withnitrogen for ˜15 min. The mixture was heated to 90° C. for 2 h. Themixture was filtered through a 2.5 g celite cartridge, washed throughwith ethyl acetate and concentrated in vacuo. The residue was taken upin dichloromethane, loaded onto a 25 g silica flash column, and elutedby silica gel chromatography in 5%-40% ethyl acetate in cyclohexane. Theappropriate fractions were collected and concentrated in vacuo to afforda yellow oil (22.9 mg, 0.040 mmol, 18.49%). This was a mixture ofdiastereoisomers. LCMS (2 min formic): Rt=1.29 min, [MH]⁺=577.

Intermediate 182: (R)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a carousel flask, evacuated and back-filled with nitrogen, was added10% Pd/C (16.90 mg, 0.016 mmol). To this was added a solution of(R)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 181, 22.9 mg, 0.040 mmol) in ethanol(1.2 mL). The flask was allowed to stir under a hydrogen atmosphere for4 h. The reaction mixture was filtered through a 2.5 g celite cartridgewith ethanol, and the eluent collected. The eluted solution wasevaporated in vacuo to afford a pale grey, transparent oil (17.9 mg,0.040 mmol). This was a mixture of diastereoisomers. LCMS (2 minFormic): Rt=0.84 min, [M]⁺=426 (loss of NH₂ ⁻).

Intermediate 183: (R)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a flask containing (R)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 182, 17.9 mg, 0.040 mmol) in1,4-dioxane (2 mL) under nitrogen was added 4-bromobenzonitrile (8.83mg, 0.049 mmol), DavePhos (6.37 mg, 0.016 mmol), Pd₂(dba)₃ (7.41 mg,8.09 μmol) and sodium tert-butoxide (11.66 mg, 0.121 mmol). The mixturewas degassed with nitrogen for ˜15 min, and then heated to 90° C. withstirring under nitrogen for ˜2 h, and then heated to 90° C. withstirring under nitrogen for ˜2 h, followed by heating at 45° C. for ˜64h. The mixture was filtered over a 2.5 g celite cartridge, washedthrough with ethyl acetate and concentrated in vacuo. The residue wastaken up in dichloromethane, loaded onto a 10 g silica flash column, andeluted by silica gel chromatography with 0%-35% ethyl acetate incyclohexane. The appropriate fractions were collected and concentratedin vacuo to afford the product (9.1 mg, 0.017 mmol, 41.4%). This was amixture of diastereoisomers. LCMS (2 min Formic): Rt=1.26 min,[MH]⁺=544.

Intermediate 184: (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a microwave vial was added (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 179, 37.7 mg, 0.085 mmol) in1,4-dioxane (2.5 mL). To this was added 2-chloro-5-methylpyrazine (21.90mg, 0.170 mmol), Pd₂(dba)₃ (15.60 mg, 0.017 mmol), sodium tert-butoxide(24.56 mg, 0.256 mmol) and DavePhos (13.41 mg, 0.034 mmol). The vesselwas sealed and heated on a microwave heater at 120° C. for 40 min. Thereaction mixture was filtered over a 2.5 g celite cartridge, washedthrough with ethyl acetate and concentrated in vacuo. The residue wasdissolved in MeOH:DMSO (1:1, 1 mL) and purified by MDAP (Formic). Thesolvent was evaporated in vacuo to give the required product (5.7 mg,12.5%). LCMS No data.

Intermediate 185: (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a dried flask under nitrogen was added (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 179, 40 mg, 0.090 mmol), DavePhos(14.23 mg, 0.036 mmol), 4-bromo-N-methylbenzamide (23.22 mg, 0.108mmol), sodium tert-butoxide (26.1 mg, 0.271 mmol) and Pd₂(dba)₃ (16.55mg, 0.018 mmol). The solids were dissolved in 1,4-dioxane (2 mL), andthe mixture bubbled through with nitrogen. The mixture was then heatedat 90° C. for ˜2 h. Further portions of Pd₂(dba)₃ (0.2 eq.) and DavePhos(0.4 eq.) were added, and the mixture continued to stir at 90° C. Thereaction mixture was cooled to rt, filtered over a 2.5 g celitecartridge, washed through with ethyl acetate and concentrated in vacuo.The sample was dissolved in MeOH:DMSO (1:1, 1 mL) and purified by MDAP(Formic). The solvent was evaporated in vacuo to give the requiredproduct (5.6 mg, 11%). This was a mixture of diastereoisomers.

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=576.

Intermediate 186: (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a microwave vessel was added (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 179, 40 mg, 0.090 mmol) and6-chloronicotinonitrile (25.04 mg, 0.181 mmol) in N-methyl-2-pyrrolidone(NMP) (1 mL). To this was added DIPEA (0.047 mL, 0.271 mmol). The vesselwas sealed and heated on a microwave heater to 150° C. for 30 min.Further portions of 6-chloronicotinonitrile (2 eq.) and DIPEA (3 eq.)were added, the vessel was resealed and heated to 150° C. for 30 min.The vessel was resealed and heated to 200° C. for 30 min. The reactionmixture was transferred to an LCMS vial, and purified by MDAP (Formic).The solvent was evaporated in vacuo to give the required product (7.0mg, 12.8%). This was a mixture of diastereoisomers.

LCMS (2 min Formic): Rt=1.20 min, [MH]⁺=545.

Intermediate 187: rac-benzyl((2S,3S,4R)-2,3-dimethyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of acetaldehyde (0.292 mL, 5.23 mmol) in anhydrous DCM (10mL) was added 4-amino-N-methylbenzamide (0.785 g, 5.23 mmol) and thereaction stirred at rt for 1 h. Diphenyl hydrogen phosphate (0.131 g,0.523 mmol) in anhydrous DCM (5 mL) was added followed by (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 1 g, 5.23mmol) in anhydrous DCM (5 mL). The mixture was then left to stir for 1.5h. The mixture was partitioned between 100 mL DCM and 25 mL sat. NaHCO₃.The organic and aqueous layers were combined and evaporated to drynessunder reduced pressure. The residue was treated with 30 mL MeOH andfiltered. The filtrate was applied to a 100 g silica gel column whichwas then dried in a vacuum oven at 40° C. The dry column was then elutedwith 0-8% MeOH in DCM to afford the crude desired product, as a whitesolid (1.15 g), which was used in the next step without furtherpurification.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=368.

Intermediate 188: rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of rac-benzyl((2S,3S,4R)-2,3-dimethyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 187, 1.15 g, 3.13 mmol), in DCM (35mL) was added DIPEA (1.64 mL, 9.39 mmol) and acetyl chloride (0.245 mL,3.44 mmol) and the mixture allowed to stir at rt for 1 h. A furtherportion of acetyl chloride (0.668 mL, 9.39 mmol) was added and themixture stirred for a further 2 h. The mixture was concentrated in vacuoto give a brown oily residue. This was purified by chromatography onsilica gel (50 g column, eluting with 0-10% MeOH in DCM) to afford thedesired product (688 mg) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=410.

Intermediate 189:rac-(2S,3R,4R)-1-acetyl-4-amino-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation, see Intermediate 188, 688 mg, 1.68 mmol) in ethanol(30 mL) was passed through a 10% Pd/C cartridge on a H-cube (rt, full H₂mode) at a flow rate of 1 mL/min. The collected solution was passedthrough the 10% Pd/C cartridge on the H-cube a second time (rt, full H₂mode) at a flow rate of 1 mL/min. The H-cube was flushed with a further10 mL EtOH, the collected solutions combined and the solvent removed byevaporation to afford the desired product as a yellow solid (429 mg).LCMS (2 min Formic): Rt=0.38 min, [MH]⁺=276.

Intermediate 190: rac-benzyl((2S,3S,4R)-2-ethyl-3-methyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of propionaldehyde (0.105 mL, 1.464 mmol) in anhydrous DCM(10 mL), was added 4-amino-N-methylbenzamide (220 mg, 1.464 mmol) andthe reaction mixture stirred at rt for 1 h. Diphenyl hydrogen phosphate(36.6 mg, 0.146 mmol) in anhydrous DCM (5 mL) was then added followed by(E)-benzyl prop-1-en-1-ylcarbamate (for a preparation see Intermediate1, 280 mg, 1.464 mmol) in anhydrous DCM (5 mL). The reaction mixture wasthen left to stir for 2 h. The reaction mixture was diluted with DCM (10mL) and washed with NaHCO₃ (40 mL) and then water (40 mL) and theorganic and aqueous layers separated. The organic layer was passedthrough a hydrophobic frit and then concentrated in vacuo to give ayellow oil which was purified by chromatography on silica gel (25 gcolumn, eluting with 0-10% MeOH in DCM) to afford the desired product asa pale yellow solid (403 mg). LCMS (2 min Formic): Rt=1.00 min,[MH]⁺=382.

Intermediate 191: rac-benzyl((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of rac-benzyl((2S,3S,4R)-2-ethyl-3-methyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 190, 403 mg, 1.056 mmol) in DCM (15mL) was added DIPEA (0.738 mL, 4.23 mmol) and acetyl chloride (0.225 mL,3.17 mmol) and the solution allowed to stir at rt for 1 h. The solutionwas concentrated in vacuo to give a brown oily residue which waspurified by chromatography on silica gel (25 g column, eluting with0-10% MeOH in DCM) followed by further purification by chromatography onsilica gel (25 g column, eluting with 80-100% EtOAC in cyclohexane) toafford the desired product as a pale yellow solid (317 mg). LCMS (2 minFormic): Rt=0.88 min, [MH]⁺=424.

Intermediate 192:rac-(2S,3R,4R)-1-acetyl-4-amino-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation, see Intermediate 191, 317 mg, 0.749 mmol) in ethanol(30 mL) was passed through a 10% Pd/C cartridge on a H-cube (rt, full H₂mode) at a flow rate of 1 mL/min. The collected solution was passedthrough the 10% Pd/C cartridge on the H-cube a second time (rt, full H₂mode) at a flow rate of 1 mL/min. The H-cube was flushed with a further10 mL ethanol, the collected solutions were combined and the solventremoved by evaporation to afford the desired product as a yellow solid(194 mg). LCMS (2 min Formic): Rt=0.43 min, [MH]⁺=290.

Intermediate 193: rac-(2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a solution of cyclopropanecarbaldehyde (0.313 mL, 4.18 mmol) inanhydrous dichloromethane (DCM) (10 mL), was added ethyl 4-aminobenzoate(691 mg, 4.18 mmol) and the reaction stirred at rt for 1 h. Diphenylhydrogen phosphate (105 mg, 0.418 mmol) in anhydrous dichloromethane(DCM) (5 mL) was added and then (E)-benzyl prop-1-en-1-ylcarbamate (fora preparation see Intermediate 1, 800 mg, 4.18 mmol) in anhydrousdichloromethane (DCM) (5 mL). The reaction was then left to stir for 18h. The reaction mixture was diluted with DCM (10 ml) and washed withNaHCO₃ (40 ml) and then water (40 mL) and the organic and aqueous layersseparated. The organic layer was passed through a hydrophobic frit andthen concentrated in vacuo to give 1.726 g of crude product as an orangeoil. This was purified by chromatography on silica (25 g, eluting withethyl acetate/cyclohexane 0-40%). Fractions containing product werecombined and concentrated in vacuo to give 1.5 g of product with someimpurities present. This was purified by chromatography on silica (50 g,eluting with ethyl acetate/cyclohexane 0-30%). The fractions containingproduct were combined and concentrated in vacuo to give 1.391 g ofproduct as a white solid.

LCMS (2 min Formic): Rt=1.23 min, [MH]⁺=409.

Intermediate 194: rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a reaction vessel rac-(2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 193, 1.391 g, 3.41 mmol), DIPEA(1.784 mL, 10.22 mmol) and acetyl chloride (0.242 mL, 3.41 mmol) wereadded in dichloromethane (DCM) (35 mL). This was left to stir at rt for45 min. A further portion of acetyl chloride (0.242 mL, 3.41 mmol) wasadded and the reaction left to stir for 30 min. Acetyl chloride (0.121mL, 1.703 mmol) was added and the reaction left to stir for 16 h. Acetylchloride (0.121 mL, 1.703 mmol) was added and the reaction left to stirfor 2 h. Acetyl chloride (0.242 mL, 3.41 mmol) was added and thereaction left to stir for 1 h. The mixture was concentrated in vacuo togive 3.1 g of crude brown solid. This was purified by chromatography onsilica (50 g, eluting with ethyl acetate/cyclohexane 0-35%). Thefractions containing mainly pure product were combined and concentratedin vacuo to give 1.433 g of product (1.368 g, 3.04 mmol, 89%) as ayellow solid.

LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=451.

Intermediate 195: rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 194, 1.1 g, 2.442 mmol) in ethanol(50 mL), 10% Pd/C (0.130 g, 1.221 mmol) was added and the reaction wasleft to stir under a hydrogen atmosphere for 16 h. The mixture wasfiltered through celite and the celite washed with ethyl acetate (3×20mL). The combined filtrates were concentrated in vacuo to give 798 mg ofcrude product. This was combined with another crude sample which wassynthesised as follows:

To solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 192, 254 mg, 0.564 mmol) in ethanol(40 mL), 10% Pd/C (0.1 g, 0.940 mmol) was added and the reaction wasleft to stir under a hydrogen atmosphere for 3 h. The reaction mixturewas filtered through celite and the celite washed with ethyl acetate(3×20 mL). The combined filtrates were concentrated in vacuo to give 206mg of crude product as an off white solid.

The combined samples were purified by chromatography on silica (25 g,eluting with 0-50% ethyl acetate/cyclohexane, followed by 0-10%DCM/ammonia in methanol (2M)). The fractions containing product werecombined and concentrated in vacuo to give 950 mg the product as ayellow oil. The sample was loaded in methanol and purified by SPE onsulfonic acid (SCX) 50 g using a sequential solvents methanol, 2Mammonia/methanol. The appropriate fractions were combined andconcentrated in vacuo to give 747 mg of the product (747 mg, 2.361mmol).

LCMS (2 min formic): Rt=0.62 min, [M]⁺=317 (loss of NH₂ ⁻).

Intermediate 196:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonylchloride

To a reaction vesselrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 131, 91 mg, 0.240 mmol) was added indichloromethane (DCM) (5 mL) under nitrogen. Thionyl chloride (1 mL,13.70 mmol) was added and the reaction left to stir at rt for 30 min.The reaction mixture was left to stir for 20 min and then concentratedin vacuo, to give 170 mg of product. This was redissolved in toluene (5mL) and the solvent evaporated (×2) to give 113 mg of product (113 mg,84% pure). This was used directly in the subsequent reaction.

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=394 (OMe adduct).

Intermediate 197:rac-(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

A sample of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 194, 4.4907 g, 4.68 mmol) wasdissolved in ethanol (10 mL). To this was added lithium hydroxide (0.224g, 9.37 mmol) slowly, and the reaction was stirred at rt for ˜1 h. Afterstirring overnight a further 0.5 eq lithium hydroxide was added (116 mg)and the mixture continued to be stirred for ˜1.5 h. The reaction mixturewas neutralised with 2M hydrochloric acid, and extracted with ethylacetate. The aqueous layer was washed a further 2 times with ethylacetate, and the combined organic layers were concentrated in vacuo toafford a yellow gum. This solid was dissolved in methanol and loadedonto a 50 g aminopropyl NH₂ SPE cartridge which had beenpre-equilibrated with methanol. The column was eluted with 3 CVs ofmethanol, and then the product was eluted off with 3CVs of 2M aceticacid in methanol. The appropriate fractions were collected andconcentrated in vacuo to afford a pale yellow oil (2.6099 g, 3.71 mmol,79%). LCMS (2 min Formic): Rt=0.94 min, [MH]⁺=423.

Intermediate 198: rac-benzyl((2S,3R,4R)-1-acetyl-6-(chlorocarbonyl)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a reaction vesselrac-(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 197, 2.604 g, 6.16 mmol) wasadded in dichloromethane (DCM) (30 mL) under nitrogen. Thionyl chloride(2 mL, 27.4 mmol) was added and the reaction left to stir at rt for 30min. The reaction mixture was left to stir for a further 20 min andthionyl chloride (0.5 mL, 6.85 mmol) was added. The reaction solutionwas concentrated in vacuo to give 2.801 g of product as a yellow solid.This was redissolved in DCM (30 mL) and the solvent evaporated (×2) togive 2.75 g of product. This was used directly in the next experiment.LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=437 (OMe adduct).

Intermediate 199:rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel containing rac-benzyl((2S,3R,4R)-1-acetyl-6-(chlorocarbonyl)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 198, 2.8 g, 6.35 mmol). Methylamine2M in THE (20 mL, 40.0 mmol) and DIPEA (12 mL, 68.7 mmol) were added andthe reaction left to stir for 15 min at rt under N₂. The solution wasconcentrated in vacuo to give 3.072 g of crude product as a yellowsolid. This was purified by chromatography on silica (100 g, elutingwith 0-100% ethyl acetate/DCM over 15 CVs). The fractions containingmostly product were combined and concentrated in vacuo to give product(540 mg). The fractions containing product and a substantial impuritywere combined and concentrated in vacuo to give impure product. This waspurified by chromatography on silica (100 g, eluting with 0-5%methanol/DCM). The fractions containing product were combined andconcentrated in vacuo to give the product as a white solid (1.408 g,3.23 mmol, 50.9%).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=436.

Intermediate 200:rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(methylcarbamoyl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 199, 1.408 g, 3.23 mmol) in ethanol(50 mL), 10% Pd/C (0.172 g) was added and the reaction was left to stirunder a hydrogen atmosphere for 16 h. The mixture was filtered throughcelite and the celite washed with ethyl acetate (3×20 mL). The combinedfiltrates were concentrated in vacuo to give 1.204 g of crude product.This was purified by chromatography on silica (25 g, eluting with 0-7% 2M ammonia in methanol/DCM).

The fractions were combined and concentrated in vacuo to give theproduct as a white solid (847 mg, 2.81 mmol, 87%). LCMS (2 min Formic):Rt=0.45 min, [M]⁺=285 (loss of NH₂ ⁻).

Intermediate 201: rac-(2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a solution of ethyl 4-aminobenzoate (2.04 g, 12.35 mmol) in anhydrousDCM (24 mL) was added acetaldehyde (0.7 mL, 12.39 mmol) and the mixturestirred under nitrogen at rt for 1 h. The reaction mixture was cooled to0° C. and to this diphenyl hydrogen phosphate (0.309 g, 1.235 mmol) inanhydrous DCM (12 mL) was added followed by (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 2.36 g,12.34 mmol) in anhydrous DCM (12 mL). The mixture was stirred at 0° C.for 1 h then allowed to warm to rt over 2 h. The reaction mixture waswashed with sat. NaHCO₃ (aq) solution (50 mL) and the aqueous layer wasextracted with DCM (30 mL). The combined organic washings were washedwith water (60 mL), dried through a hydrophobic frit and concentrated invacuo. The gum was dissolved in DCM (10 mL) which was loaded onto a 100g silica cartridge and purified using a gradient of 0-60% EtOAc incyclohexane over 10 CVs. The appropriate fractions were combined and thesolvent removed by rotary evaporation to give 4.2 g solid. The solid wasdissolved in hot EtOAc (10 mL) and allowed to cool to rt. The resultingprecipitate was filtered, washed with EtOAc (10 mL) and dried in avacuum oven to give the title compound as a white amorphous solid (1.46g, 56% purity).

LCMS (2 min HpH): Rt=1.20 min, [MH]⁺=383.

Intermediate 202: rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of rac-(2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(fora preparation see Intermediate 201, 1.46 g, 3.82 mmol) in aceticanhydride (10 mL, 106 mmol) was stirred under nitrogen at 140° C. for 1h. The reaction mixture was allowed to cool to rt and diluted with EtOAc(20 mL). The organic layer was stirred vigorously with 1 M NaOH (aq) (20mL), separated and the process repeated. The organic layer was washedwith water (20 mL), dried through a hydrophobic frit and the solventevaporated under vacuum. The oil was dissolved in DCM (8 mL), applied toa 100 g silica cartridge and purified using a gradient of 0-80% EtOAc incyclohexane over 8 CVs. The appropriate fractions were combined and thesolvent removed by rotary evaporation to give the title compound as anoff-white foam (1.39 g, 75% purity). LCMS (2 min Formic): Rt=1.11 min,[MH]⁺=425.

Intermediate 203: rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 202, 1.39 g, 3.27 mmol) in ethanol(15 mL) was added to 10 wt. % palladium on carbon (140 mg, 1.316 mmol)and the mixture stirred under an atmosphere of hydrogen at rt for 16 h.The reaction mixture was filtered through celite and the cake washedwith EtOH (80 mL). The filtrate was evaporated in vacuo and the gumdissolved in MeOH (5 mL). The solution was applied to aMeOH-preconditioned 25 g SCX-2 cartridge. The cartridge was washed withMeOH (40 mL) followed by 2M ammonia in MeOH solution (40 mL). The basicwash was evaporated under vacuum and dried in a vacuum oven to give thetitle compound as a yellow oil (943 mg, 3.25 mmol, 99%, 87% purity).

LCMS (2 min HpH): Rt=0.82 min, [M]⁺=274 (loss of NH₂ ⁻).

Intermediate 204: rac-(2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a solution of ethyl 4-aminobenzoate (2.02 g, 12.23 mmol) in anhydrousDCM (24 mL) was added propionaldehyde (0.91 mL, 12.22 mmol) and themixture stirred under nitrogen at r.t. for 1 h. The reaction mixture wascooled to 0° C. and to this diphenyl hydrogen phosphate (0.306 g, 1.223mmol) in anhydrous DCM (12 mL) was added followed by (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 2.34 g,12.24 mmol) in anhydrous DCM (12 mL). The mixture was stirred at 0° C.for 1 h then allowed to warm to rt over 2 h. The reaction mixture waswashed with sat. NaHCO₃ (aq) solution (50 mL) and the aqueous layerextracted with DCM (30 mL). The organics were combined, washed withwater (60 mL), dried through a hydrophobic frit and concentrated invacuo. The solid was dissolved in hot EtOAc (10 mL) and the solutionallowed to cool to rt. The resulting precipitate was isolated by vacuumfiltration and dried in a vacuum oven to give the title compound as awhite amorphous solid (2.22 g, 5.60 mmol, 46%).

LCMS (2 min HpH): Rt=1.26 min, [MH]⁺=397.

Intermediate 205: rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of rac-(2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(fora preparation see Intermediate 204, 2.10 g, 5.30 mmol) in aceticanhydride (15 mL, 159 mmol) was stirred under nitrogen at 140° C. for2.5 h. The reaction mixture was allowed to cool to rt and diluted withEtOAc (30 mL). The organic layer was stirred vigorously with 1 M NaOH(aq) (30 mL), separated and the process repeated. The organic layer waswashed with water (30 mL), dried through a hydrophobic frit and thesolvent evaporated under vacuum. The oil was dissolved in DCM (8 mL),applied to a 100 g silica cartridge and purified using a gradient of0-100% EtOAc in cyclohexane over 10 CVs. The appropriate fractions werecombined and the solvent removed by rotary evaporation to give the titlecompound as an off-white foam (2.33 g, 5.31 mmol, 100%). LCMS (2 minHpH): Rt=1.18 min, [MH]⁺=439.

Intermediate 206: rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 205, 2.33 g, 5.31 mmol) in ethanol(25 mL) was added to 10 wt. % palladium on carbon (233 mg, 2.189 mmol)and the mixture stirred under an atmosphere of hydrogen at rt for 24 h.The reaction mixture was filtered through celite and the cake washedwith EtOH (80 mL). The filtrate was evaporated in vacuo and the gumdissolved in MeOH (5 mL). The solution was applied to aMeOH-preconditioned 50 g SCX-2 cartridge. The cartridge was washed withMeOH (80 mL) followed by 2M ammonia in MeOH solution (80 mL). The basicwash was evaporated under vacuum and dried in a vacuum oven to give thetitle compound as a yellow oil (1.62 g, 5.32 mmol, 100%).

LCMS (2 min HpH): Rt=0.89 min, [M]⁺=288 (loss of NH₂ ⁻).

Intermediate 207:rac-1-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)thiourea

rac-1-((2S,3R,4RS)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(For a preparation see Intermediate 14, 75 mg, 0.307 mmol) and benzoylisothiocyanate (0.041 mL, 0.307 mmol) in DCM (0.5 mL) were stirred at rtovernight. The solvent was evaporated and the residue redissolved inmethanol (0.5 mL), THE (0.5 mL) and water (0.5 mL). Potassium carbonate(212 mg, 1.535 mmol) was added and the reaction stirred at rt for 4 h.The solvent was evaporated, the residue partitioned between water (10mL) and EtOAc (20 mL) and the aqueous layer extracted with EtOAc (2×20mL). Combined organics were washed with brine, dried (MgSO₄) andevaporated to dryness. This was purified by silica chromatography (0-7%2M NH₃ in MeOH/DCM) to afford the product (70 mg) as a clear oil. LCMS(2 min HpH): Rt=0.75 min, [MH]⁺=304.

Intermediate 208: benzyl((2S,3S,4R)-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of 4-bromoaniline (3 g, 17.44 mmol) and acetaldehyde (1.468mL, 26.2 mmol) in dry DCM (110 mL) was stirred under nitrogen at rt for1 h and then cooled to 0° C. Solutions of (11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.101 g, 0.174mmol) in dry DCM (20 mL) followed by (E)-benzyl prop-1-en-1-ylcarbamate(for a preparation see Intermediate 1, 3.67 g, 19.18 mmol) in dry DCM(20 mL) were added. The reaction was stirred at 0° C. overnight. Thereaction mixture was warmed to rt, washed with sat. aq. NaHCO₃ (100 mL)and the aqueous layer was extracted with DCM (100 mL). The combinedorganics were dried through a hydrophobic frit and the solvent wasremoved by rotary evaporation to leave the crude product. The crudematerial was loaded onto a 100 g silica column and eluted using agraduating solvent system of 0-30% EtOAc/cyclohexane. Combination andevaporation of the desired fractions gave the product. This wasdissolved in a minimum of hot EtOAc (˜10 mL) and diluted withcyclohexane (70 mL). The solution was allowed to cool and placed in thefridge overnight. The resulting white crystals were filtered washingwith cool 10% EtOAc/cyclohexane before being dried in the vacuum oven togive the product as a white crystalline solid (2.1 g). Analysis bychiral HPLC was undertaken using a 250×4.6 mm Chiralpak IC columneluting with 10% ethanol in heptanes (plus 0.1% isopropylamine) at aflow rate of 1 mL/min. Peak 1/minor enantiomer (3.1%) eluted at 6.4 min,and Peak 2/major enantiomer (96.9% by UV) eluted at 8.1 min. Thisindicated the product had a ee of 94%.

LCMS (2 min Formic): Rt=1.22 min, [MH]⁺=389, 391.

Intermediate 209: benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of benzyl((2S,3S,4R)-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 208, 2.0 g, 5.14 mmol) and pyridine(1.25 mL, 15.4 mmol) in DCM (37 mL) was treated with acetyl chloride(0.88 mL, 12.3 mmol) and the reaction mixture stirred at rt for 3 h. Thereaction mixture was washed with HCl (1M, 40 mL), followed by saturatedNaHCO₃ (aq., 40 mL) and the organic layer isolated then concentratedunder reduced pressure to give the desired product as a white solid(2.22 g). LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=431, 433.

Intermediate 210: benzyl((2S,3S,4R)-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of DavePhos (0.091 g, 0.232 mmol), morpholine (0.404 mL, 4.64mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 209, 1.00 g, 2.32 mmol) andPd₂(dba)₃ (0.212 g, 0.232 mmol) in toluene (30 mL) was treated withsodium tert-butoxide (0.446 g, 4.64 mmol) and the reaction mixtureheated at 110° C. for 1 hr then concentrated under reduced pressure.Material was suspended in EtOAc then filtered through a pad of celite,which was washed with EtOAc then combined EtOAc washes concentratedunder reduced pressure. Crude material was purified by silica columnchromatography, eluting with a gradient 0 to 100% of EtOAc incyclohexane to give the desired product as clear, colourless gum (360mg). LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=438.

Intermediate 211:rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 170, 1.1 g, 90% pure) and benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 210, 0.36 g, 94% ee) in ethanol (70mL) was passed through a 10% Pd/C cartridge on an H-cube (rt, full H₂mode) then recycled through the machine for a total of 6 hr. Theresulting filtrate was concentrated under reduced pressure to givedesired product as a pale yellow amorphous solid (1.0 g, 72% purity,˜25% ee). LCMS (2 min Formic): Rt=0.46 min, [MH]⁺=304.

Intermediates 212: tert-butyl4-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A solution of DavePhos (9 mg, 0.023 mmol), tert-butylpiperazine-1-carboxylate (0.086 mL, 0.464 mmol), benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 209, 100 mg, 0.232 mmol, Pd₂(dba)₃(21 mg, 0.023 mmol) and sodium tert-butoxide (45 mg, 0.468 mmol) intoluene (2 mL) was heated at 110° C. under nitrogen for 1 h. Separatelya solution of DavePhos (0.091 g, 0.23 mmol), tert-butylpiperazine-1-carboxylate (0.86 mL, 4.64 mmol), benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(1 g, 2.318 mmol) and Pd₂(dba)₃ (0.212 g, 0.232 mmol) in toluene (30 mL)was treated with sodium tert-butoxide (0.446 g, 4.64 mmol) and thereaction mixture heated at 110° C. for 1 h then concentrated underreduced pressure. Material was suspended in EtOAc, combined with theprevious smaller batch of material, and combined batches filteredthrough a 10 g pad of celite which was washed with further EtOAc.Combined EtOAc washes were concentrated under reduced pressure and crudematerial was purified by silica column chromatography, eluting with a 0to 100% gradient to give the product (360 mg). LCMS (2 min Formic):Rt=1.18 min, [MH]⁺=537.

Intermediate 213: tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A solution of tert-butyl4-((2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 212, 360 mg, 0.671 mmol) in ethanol(14 mL) was passed through a 10% Pd/C cartridge on an H-cube (RT, fullH₂ mode) then recycled through the machine for a total of 8 h. Theresulting filtrate was combined with the previous batch of tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(400 mg), concentrated under reduced pressure to give desired product asa grey/brownish amorphous solid (550 mg, 80% purity).

LCMS (2 min Formic): Rt=0.71 min, [MH]⁺=403.

Intermediate 214: tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A microwave vial was charged with tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 213, 69 mg, 0.151 mmol) in1,4-dioxane (2 mL) followed by 4-bromobenzonitrile (51 mg, 0.280 mmol),then sodium tert-butoxide (27 mg, 0.281 mmol), DavePhos (12 mg, 0.030mmol), and Pd₂(dba)₃ (26 mg, 0.028 mmol). The reaction mixture washeated to 100° C. for 45 min using a microwave reactor, then dilutedwith EtOAc and filtered through a pad of celite. The celite pad waswashed with EtOAc (10 mL) and the filtrate concentrated under reducedpressure. The residue was purified by MDAP (Formic). The desiredfractions were combined and evaporated in vacuo to afford the desiredproduct as a white solid (22 mg). LCMS (2 min Formic): Rt=1.15 min,[MH]⁺=504.

Intermediate 215: tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A microwave vial was charged with tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 213, 69 mg, 0.151 mmol) in1,4-dioxane (2 mL) followed by 2-bromo-4-methylpyrimidine (49 mg, 0.283mmol), then sodium tert-butoxide (27 mg, 0.281 mmol), DavePhos (12 mg,0.030 mmol), and Pd₂(dba)₃ (26 mg, 0.028 mmol). The reaction mixture washeated to 100° C. for 45 min using a microwave reactor, then dilutedwith EtOAc and filtered through a pad of celite. The celite pad waswashed with EtOAc (10 mL) and the filtrate concentrated under reducedpressure. The residue was purified by MDAP (Formic). The desiredfractions were combined and evaporated in vacuo to afford the desiredproduct as a pale brown gum (14 mg). LCMS (2 min Formic): Rt=1.01 min,[MH]⁺=495.

Intermediate 216: tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A microwave vial was charged with tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 213, 69 mg, 0.151 mmol) in1,4-dioxane (2 mL) followed by 4-bromo-N-methylbenzamide (61 mg, 0.285mmol), then sodium tert-butoxide (27 mg, 0.281 mmol), DavePhos (12 mg,0.030 mmol), and Pd₂(dba)₃ (26 mg, 0.028 mmol). The reaction mixture washeated to 100° C. for 45 min using a microwave reactor, then dilutedwith EtOAc and filtered through a pad of celite. The celite pad waswashed with EtOAc (10 mL) and the filtrate concentrated under reducedpressure. The residue was purified by MDAP (Formic). The desiredfractions were combined and evaporated in vacuo to afford the desiredproduct as a pale brown gum (13 mg). LCMS (2 min Formic): Rt=0.99 min,[MH]⁺=536.

Intermediate 217: tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A microwave vial was charged with tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 213, 69 mg, 0.151 mmol) in1,4-dioxane (2 mL) followed by 2-chloro-5-methylpyrazine (37 mg, 0.288mmol), then sodium tert-butoxide (27 mg, 0.281 mmol), DavePhos (12 mg,0.030 mmol), and Pd₂(dba)₃ (26 mg, 0.028 mmol). The reaction mixture washeated to 100° C. for 45 min using a microwave reactor, then dilutedwith EtOAc and filtered through a pad of celite. The celite pad waswashed with EtOAc (10 mL) and the filtrate concentrated under reducedpressure. The residue was purified by MDAP (Formic). The desiredfractions were combined and evaporated in vacuo to afford the desiredproduct as a pale brown gum (10 mg). LCMS (2 min Formic): Rt=1.02 min,[MH]⁺=495.

Intermediate 218: benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of 4-bromoaniline (3 g, 17.44 mmol) andcyclopropanecarbaldehyde (1.303 mL, 17.44 mmol) in dry DCM (60 mL) wasstirred under nitrogen at rt in a 250 mL Lara large scale reactor vesselfor 90 min and then cooled to 0° C. Solutions of (11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.101 g, 0.174mmol) in dry DCM (20 mL) followed by (E)-benzyl prop-1-en-1-ylcarbamate(fora preparation see Intermediate 1, 3.67 g, 19.18 mmol) in dry DCM (20mL) were added. The reaction was stirred at 0° C. for 40 h. The reactionmixture was warmed to rt, washed with sat. aq. NaHCO₃ (150 mL) and theaqueous layer was extracted with DCM (2×100 mL). The combined organicswere dried through a hydrophobic frit and the solvent was removed byrotary evaporation to leave the crude product. The crude product wasrecrystallised (dissolved in ˜50 mL refluxing EtOAc, 50 mL cyclohexaneadded and cooled, the resulting crystals were then washed with coldcyclohexane) to afford the product (4.89 g, 11.77 mmol, 67.5%) as whiteneedles. Analysis by chiral HPLC was undertaken using a 250×4.6 mmChiralpak IC column eluting with 10% ethanol in heptane at a flow rateof 1 mL/min. Peak 1/minor enantiomer (<0.5% by UV) eluted at 6.5 min,and Peak 2/major enantiomer (>99.5% by UV) eluted at 11.5 min. Thisindicated the product had an ee of 99%. LCMS (2 min HpH): Rt=1.32 min,[MH]⁺=415, 417.

Intermediate 219: benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 218, 4.8 g, 11.56 mmol) and pyridine(2.80 mL, 34.7 mmol) in anydrous dichloromethane (DCM) (75 mL) wastreated with acetyl chloride (0.986 mL, 13.87 mmol). The mixture wasstirred at rt under an atmosphere of nitrogen overnight. The reactionwas incomplete so further acetyl chloride (0.986 mL, 13.87 mmol) wasadded. The reaction mixture was transferred to a separating funnel andwashed with 1M aq. HCl (75 mL) followed by sat. aq. NaHCO₃ (75 mL) andbrine (75 mL). The organic layer was dried through a hydrophobic fritand the solvent was removed by rotary evaporation to give the crudeproduct as a white solid (5.2 g). This was pure enough to use insubsequent steps.

LCMS (2 min Formic): Rt=1.19 min, [MH]⁺=457, 459.

Intermediate 220: (S)-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a dried flask under nitrogen was added (S)-tert-butyl2-methylpiperazine-1-carboxylate (0.531 g, 2.65 mmol), benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 219, 1.01 g, 2.208 mmol), sodiumtert-butoxide (0.424 g, 4.42 mmol), Pd₂(dba)₃ (115 mg, 0.126 mmol) andDavePhos (0.149 g, 0.378 mmol). The solids were all dissolved in1,4-dioxane (10 mL), and the mixture was degassed with nitrogen for ˜15min. The mixture was then heated at 90° C. for 16 h. The reactionmixture was allowed to cool, washed through a 10 g celite cartridge withethyl acetate and concentrated in vacuo to afford an orange oil. Theresidue was dissolved in methanol and loaded onto a 50 g SCX-2 SPEcartridge which had been pre-equilibrated with methanol. The column waseluted with methanol (180 mL), and then 2M methanolic ammonia (180 mL).The appropriate fractions were collected and concentrated in vacuo. Thecrude residue was taken up in dichloromethane, loaded onto a 50 g silicaflash column, and eluted by silica gel chromatography with 4-8% 2MNH₃/MeOH in dichloromethane. The appropriate fractions were collectedand concentrated in vacuo to afford a yellow crystalline solid (158.4mg, 0.358 mmol, 16.21%). LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=443.

Intermediate 221: (S)-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a dried flask under nitrogen was added DavePhos (40.0 mg, 0.102mmol), (S)-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 220, 75 mg, 0.169 mmol),2-bromo-5-fluoropyridine (35.8 mg, 0.203 mmol), Pd₂(dba)₃ (31.0 mg,0.034 mmol) and sodium tert-butoxide (48.9 mg, 0.508 mmol). Thereactants were dissolved in 1,4-dioxane (3 mL), and the solution washeated under nitrogen at 90° C. for 90 min. The mixture continued to bestirred at 45° C. overnight. A further portion of2-bromo-5-fluoropyridine (1.2 eq) was added, and the mixture was stirredat 45° C. for ˜1 h. A further portion of Pd₂(dba)₃ (0.2 eq) and DavePhos(0.6 eq) were added, and the mixture stirred at 90° C. for ˜1 h. Afurther portion of 2-bromo-5-fluoropyridine (1.0 eq) was added and themixture continued to stir at 90° C. for ˜30 min. The reaction mixturewas then filtered through a 2.5 g celite cartridge, washed through withethyl acetate, and concentrated in vacuo. The residue was taken up indichloromethane and loaded onto a 25 g silica flash column, and elutedby silica gel chromatography using 10-30% ethyl acetate in cyclohexane.The appropriate fractions were combined and concentrated in vacuo toafford the desired product (33.6 mg, 0.062 mmol, 36.9%). LCMS (2 minFormic): Rt=1.23 min, [MH]⁺=538.

Intermediate 222: (S)-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a dried flask under nitrogen was added DavePhos (40.0 mg, 0.102mmol), (S)-tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 220, 75 mg, 0.169 mmol),2-bromo-6-methoxypyridine (0.025 mL, 0.203 mmol), Pd₂(dba)₃ (31.0 mg,0.034 mmol) and sodium tert-butoxide (48.9 mg, 0.508 mmol). Thereactants were dissolved in 1,4-dioxane (3 mL), and the solution washeated under nitrogen at 90° C. for 90 min. The reaction mixture wasallowed to cool, filtered over a 2.5 g celite cartridge, and washedthrough with ethyl acetate. The solution was concentrated in vacuo toafford a dark brown oil. This crude residue was dissolved indichloromethane, loaded onto a 10 g silica flash cartridge and eluted bysilica gel chromatography in 0-30% ethyl acetate in cyclohexane. Theappropriate fractions were collected and concentrated in vacuo to afforda yellow oil (62.8 mg, 0.114 mmol, 67.4%).

LCMS (2 min Formic): Rt=1.32 min, [MH]⁺=550.

Intermediate 223: (2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a solution of cyclopropanecarbaldehyde (1.357 mL, 18.16 mmol) inanhydrous dichloromethane (DCM) (35.6 ml), was added ethyl4-aminobenzoate (3 g, 18.16 mmol) and the reaction stirred at RT for 1hr. The reaction was cooled to 0° C. (11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.105 g, 0.182mmol) in anhydrous dichloromethane (DCM) (17.82 mL) was added and then(E)-benzyl prop-1-en-1-ylcarbamate (for a preparation see Intermediate1, 3.47 g, 18.16 mmol) in anhydrous dichloromethane (DCM) (17.82 ml).The reaction was then left to stir at 0° C. for 18 h under N₂. Thereaction mixture was washed with sat. NaHCO₃ solution (60 mL) and theaqueous layer extracted with DCM (3×60 mL). The combined organics weredried through a hydrophobic frit and concentrated in vacuo. The crudeproduct was recrystallised from EtOAc/cyclohexane to afford the product(5.13 g) as white crystals. Analysis by chiral HPLC was undertaken usinga 250×4.6 mm Chiralpak IC column eluting with 30% ethanol in heptane ata flow rate of 1 mL/min. Peak 1/minor enantiomer (<0.5%) eluted at 5.9min, and Peak 2/major enantiomer (>99.5% by UV) eluted at 11.8 min. Thisindicated the product had an ee of >99%. LCMS (2 min HpH): Rt=1.27 min,[MH]⁺=409.

Intermediate 224: (2S,3S,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of (2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 223, 5.08 g, 12.44 mmol) andpyridine (3.02 ml, 37.3 mmol) in dichloromethane (DCM) (100 ml) wastreated with acetyl chloride (1.061 ml, 14.92 mmol). The mixture wasstirred under N₂ at rt for 18 h. Incomplete conversion so 300 μL acetylchloride added and the reaction stirred for 2 h. The reaction mixturewashed with 1M aq. HCl (50 mL) followed by sat. aq. NaHCO₃ (50 mL) andwater (50 mL). The organic layer was dried through a hydrophobic fritand the solvent was removed in vacuo to give the product (5.55 g) as ayellow solid. LCMS (2 min HpH): Rt=1.19 min, [MH]⁺=451.

Intermediate 225: ((2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of (2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(For a preparation see Intermediate 224, 5.52 g, 12.25 mmol) in ethanol(245 mL) was passed through a Thales H-cube Flow Hydrogenator with a 10%Pd/C CatCart in full H₂ mode at a rate of 1 mL/min. The solvent wasevaporated to afford the product (3.945 g, 11.85 mmol, 97%) as a yellowoil. LCMS (2 min HpH): Rt=0.91 min, [MH]⁺=300.

Intermediate 226:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 100 mg, 0.264 mmol) and HATU(120 mg, 0.316 mmol) in N,N-dimethylformamide (DMF) (3 mL) was addedtert-butyl (2-aminoethyl)(methyl)carbamate (0.057 mL, 0.316 mmol) andDIPEA (0.184 mL, 1.054 mmol). The reaction mixture was stirred at rt for1 h. The reaction mixture was partitioned between ether (25 mL) andwater (50 mL) and the aqueous extracted with ether (3×25 mL). Thecombined organics were washed with brine (10 mL), dried over magnesiumsulphate and evaporated in vacuo to afford the product (132 mg). LCMS (2min HpH): Rt=1.11 min, [MH]⁺=536.

Intermediate 227: (2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of 2-chloro-4-methylpyrimidine (12.96 g, 101 mmol), potassiumfluoride (7.99 g, 137 mmol), (2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 29 g, 92 mmol), 18-crown-6(12.11 g, 45.8 mmol) and DIPEA (27.2 mL, 156 mmol) in dimethyl sulfoxide(DMSO) (145 mL) was added to a flask and heated to 140° C. for 22 h. Thereaction was allowed to cool and then was partitioned between water (300mL) and ethyl acetate (300 mL). The layers were separated and theaqueous layer further extracted with ethyl acetate (2×300 mL). Thecombined organics were washed with brine (4×300 mL), dried (MgSO₄),filtered and concentrated in vacuo. Purification was undertaken by flashcolumn chromatography. The crude material was loaded onto a 340 g silicacolumn and eluted using a graduating solvent system of 0-100% ethylacetate in cyclohexane. The desired fractions were combined andconcentrated to leave the product as a pale yellow foam (29 g).

LCMS (2 min Formic): Rt=0.99 min, [MH]⁺=409.

Intermediate 228:2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine

To a solution of (6-bromopyridin-2-yl)methanol (250 mg, 1.330 mmol) andimidazole (362 mg, 5.32 mmol) in anhydrous DMF (1.2 mL) was addedTBDMSCl (240 mg, 1.596 mmol) and the mixture stirred in a stopperedvessel at rt for 45 min. The mixture was diluted with water (10 mL) andextracted with ether (2×10 mL). The organic extracts were combined andwashed with 10% LiCl (aq) (2×10 mL). The organic layer was dried througha hydrophobic frit and concentrated under reduced pressure. The residuewas loaded in cyclohexane (4 mL) and purified on a silica cartridge (50g) using a gradient of 0-100% DCM in cyclohexane over 10 CV. Theappropriate fractions were combined and the solvent evaporated in vacuoto give the title compound as a colourless mobile oil (349 mg, 1.16mmol, 87%). LCMS (2 min Formic): Rt=1.48 min, [MH]⁺=302/304.

Intermediate 229: benzyl((2S,3S,4R)-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of 4-aminobenzonitrile (5 g, 42.3 mmol) inanhydrous dichloromethane (150 mL), cyclopropanecarbaldehyde (4.74 mL,63.5 mmol) was added. The reaction mixture was stirred under nitrogenfor 30 min. The reaction mixture was then cooled in an ice bath, (11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (0.489 g, 0.846 mmol) and (E)-benzyl prop-1-en-1-ylcarbamate(for a preparation see Intermediate 1, 8.90 g, 46.6 mmol) were added.The reaction mixture was stirred under nitrogen for 1 h. The reactionsuspension was filtered and the cream solid obtained was dried in avacuum oven to provide the title compound (10.24 g, 60%). Analysis bychiral HPLC was undertaken using a 250×4.6 mm Chiralpak IA columneluting with 40% ethanol in heptane at a flow rate of 1 mL/min. Peak1/major enantiomer (>99.5%) eluted at 4.7 min, and Peak 2/minorenantiomer (<0.5% by UV) eluted at 10.0 min. This indicated the producthad an ee of >99%. LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=362.

Intermediate 230: benzyl((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred suspension of benzyl((2S,3S,4R)-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 229, 10.24 g, 28.3 mmol) inanhydrous dichloromethane (200 mL), pyridine (6.87 mL, 85 mmol) wasadded. The reaction suspension was stirred under nitrogen and cooled inan ice bath. To the reaction suspension, acetyl chloride (2.417 mL, 34.0mmol) was added. The reaction suspension was stirred overnight. To thereaction mixture, pyridine (2.291 mL, 28.3 mmol) was added. The reactionmixture was cooled in an ice bath and acetyl chloride (2.417 mL, 34.0mmol) was added. The reaction suspension was stirred under nitrogen for3.5 h The reaction mixture was left without stirring under nitrogenovernight. The reaction mixture was washed with 2M HCl (once), water(once) and sodium hydrogen carbonate (once). The organic layer wasdried, concentrated in vacuo, dissolved in DCM, loaded onto a SNAP (340g) Biotage silica cartridge and eluted with cyclohexane/ethyl acetate(12%-50%). The correct fractions were concentrated in vacuo to give thetitle compound as a white foam (8.7 g, 69%).

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=404.

Intermediate 231:(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

Benzyl((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 230, 13.96 g, 34.6 mmol) was takenup in 1M TBAF in THE (173 mL, 173 mmol) and allowed to stir at 65° C.under N₂ for 2.5 h. The reaction was concentrated and then partitionedbetween sat aq. NaHCO₃ (100 mL) and DCM (100 mL). The aqueous layer wasextracted with further DCM (100 mL) and the combined organics werewashed with water (100 mL) and then passed through a hydrophobic fritand concentrated in vacuo. The crude material was dissolved in minimalMeOH and split into 3 equal volumes. Each volume was applied to a SCXcartridge (70 g) which had been pre-conditioned with MeOH (70 mL). Thecartridges were washed with MeOH (100 mL) and 2M NH₃ in MeOH (100 mL).The ammonia washes of the first two runs were combined and concentratedin vacuo to give batch 1 of the title compound (5.1 g, 55%). The ammoniawash of the third run appeared to be impure so it was concentrated invacuo and the SCX process was repeated to give batch 2 of the titlecompound (1.6 g, 17%). LCMS (2 min Formic): Rt=0.47 min, [M-NH₂]⁺=253.

Intermediate 232:(2S,3R,4R)-1-acetyl-4-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A mixture of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 150 mg, 0.557 mmol), sodiumtert-butoxide (107 mg, 1.114 mmol), Pd(QPhos)₂ (24 mg, 0.016 mmol) and2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (for apreparation see Intermediate 228, 253 mg, 0.835 mmol) in anhydroustoluene (1 mL) was evacuated and purged with nitrogen (×3) and stirredunder nitrogen at 50° C. for 2 h. The reaction mixture was filteredthrough a 2.5 g Celite cartridge and the cartridge then washed withEtOAc (25 mL). The filtrate was evaporated in vacuo and the gumdissolved in DCM (1 mL). The solution was loaded onto a silica cartridge(50 g) and purified using a gradient of 0-100% EtOAc in cyclohexane over10 CV. The appropriate fractions were combined and the solvent removedby rotary evaporation to give the title compound as an off-white foam(186 mg, 0.379 mmol, 68%). LCMS (2 min Formic): Rt=1.24 min, [MH]⁺=491.

Intermediate 233: tert-butyl4-((6-bromopyridin-2-yl)methyl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (225 mg, 1.210mmol) and 6-bromopicolinaldehyde (150 mg, 0.806 mmol) in dichloromethane(5 mL) left stirring for 45 min, was added sodium triacetoxyborohydride(256 mg, 1.210 mmol). The mixture was stirred at rt for 17 h. Furthertert-butyl piperazine-1-carboxylate (150 mg, 0.806 mmol) was added tothe mixture and the reaction left stirring at rt for 1 h. Then sodiumtriacetoxyborohydride (171 mg, 0.806 mmol) was added and reactionmixture left stirring at rt for 1 h. As the reaction didn't show furtherprogression, some acetic acid (4.62 μL, 0.081 mmol) was added and thereaction left stirring for 1 h. The mixture was concentrated in vacuo toafford a white gum (661 mg). The resulting crude product was quenchedwith sat. NaHCO₃. The aqueous phase was extracted with DCM (×3). Theorganic layers were combined, filtered through a hydrophobic frit andthe volatiles removed under reduced pressure to afford a yellow gum(399.8 mg). The crude product was purified by silica chromatographyusing a Biotage Isolera. The product was loaded onto a silica SNAPcartridge (50 g) and eluted with 5-25% EtOAc in cyclohexane over 20 CV.The relevant fractions were combined and the volatiles were removedunder reduce pressure to afford the title compound as a colourless gum(139.4 mg).

LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=356/358.

Intermediate 234: tert-butyl4-((6-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2-yl)methyl)piperazine-1-carboxylate

In a 50 mL RB Flask were added(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 50.5 mg, 0.187 mmol),tert-butyl 4-((6-bromopyridin-2-yl)methyl)piperazine-1-carboxylate (forapreparation see Intermediate 233, 62.2 mg, 0.175 mmol), Pd₂dba₃ (24.1mg, 0.026 mmol), sodium tert-butoxide (39.3 mg, 0.409 mmol) and QPhosligand (17 mg, 0.024 mmol) in toluene (3 mL). The reaction mixture wasstirred at 50° C., under nitrogen, overnight. Further Pd₂dba₃ (17.17 mg,0.019 mmol), sodium tert-butoxide (9.01 mg, 0.094 mmol) and QPhos ligand(13.36 mg, 0.019 mmol) were added and reaction mixture was left stirringunder the same conditions for 2 h. The reaction mixture was allowed tocool to rt and allowed to stand overnight. The reaction mixture wasfiltered through a celite cartridge and partitioned between water andEtOAc. The aqueous phase was extracted with EtOAc (×3). The organiclayers were combined and washed with brine, dried over Na₂SO₄, filteredthrough a hydrophobic frit and the volatiles removed under reducepressure to afford the crude product as an orange gum (161.3 mg). Theresulting crude product was purified by silica chromatography using aBiotage Isolera. The product was loaded on a silica SNAP cartridge (25g) and eluted with 1-5% 2M NH₃ in MeOH in DCM over 20 CV. The relevantfractions were combined and the volatiles were removed under reducedpressure to afford the title compound as a yellow gum (88.8 mg). LCMS (2min Formic): Rt=0.88 min, [MH]⁺=546.

Intermediate 235: 4-((6-bromopyridin-2-yl)methyl)morpholine

A solution of 6-bromopicolinaldehyde (2.9368 g, 15.79 mmol) andmorpholine (1.376 mL, 15.79 mmol) in 2-methyltetrahydrofuran (2-MeTHF)(30 mL) under nitrogen was charged with sodium triacetoxyborohydride(5.3635 g, 25.3 mmol) and allowed to stir for 2 h at 20° C. The reactionmixture was then diluted with ethyl acetate (10 mL) and saturatedaqueous sodium bicarbonate (20 mL). The organic layer was isolated anddried by passing through a hydrophobic frit, and then concentrated invacuo to give the crude product. The crude product was applied to asilica column (100 g) which was eluted with Hex/EtOAc (0-100%, 80 minrun). The appropriate fractions were combined and concentrated in vacuoto give a clear oil, which still contained impurities by NMR. In aseparate vessel, a solution of 6-bromopicolinaldehyde (2.9967 g, 16.11mmol) and morpholine (1.400 mL, 16.07 mmol) in 2-methyltetrahydrofuran(2-MeTHF) (50 mL) under nitrogen was charged with sodiumtriacetoxyborohydride (4.6139 g, 21.77 mmol) and allowed to stir for 14h at 20° C. The reaction mixture was then diluted with ethyl acetate (10mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layerwas isolated and dried by passing through a hydrophobic frit, thenconcentrated in vacuo to give the crude product. The crude product waspurified on a silica column (100 g), eluting with Hex/EtOAc (0-100%, 60min run). The appropriate fractions were combined and concentrated invacuo to give a oils from clear oil. The two clear both reactions werecombined and passed through an aminopropyl SPE cartridge which waseluted with 70 mL of MeOH. This solution was concentrated in vacuo andleft to dry under high vacuum for 30 min, to give the title compound asa clear oil (3.9456 g). LCMS (2 min Formic): Rt=0.33 min, [MH]⁺=257/259.

Intermediate 236: 1-(6-bromopyridin-2-yl)-N,N-dimethylmethanamine

A solution of dimethylamine hydrochloride (477 mg, 5.85 mmol) and6-bromopicolinaldehyde (439 mg, 2.360 mmol) in dichloromethane (10 mL)was left stirring for 2 h over activated molecular sieves. Sodiumtriacetoxyborohydride (750 mg, 3.54 mmol) was then added and the mixturestirred at rt for ˜18 h. The mixture was concentrated in vacuo to afforda white/yellow gum (1.0647 g). The resulting crude product was quenchedwith sat. NaHCO₃. The aqueous phase was extracted with DCM (×3). Theorganic layers were combined, filtered through a hydrophobic frit andthe volatiles removed under reduced pressure to afford the titlecompound as a yellow gum (328 mg) which was used crude in the subsequentreaction. LCMS (2 min Formic): Rt=0.34 min, [MH]⁺=215/217.

Intermediate 237: 2-chloro-5-methoxy-4-methylpyrimidine

To a solution of 2,4-dichloro-5-methoxypyrimidine (1 g, 5.59 mmol) intetrahydrofuran (32.2 mL)/N-methyl-2-pyrrolidone (2.424 mL) was addedferric acetylacetonate (0.197 g, 0.559 mmol) and the mixture was cooledto 0° C. under nitrogen. Then methylmagnesium bromide (2.62 mL, 8.38mmol, 3.2 M in MeTHF) was added dropwise. The mixture was stirred for 30min under nitrogen at 0° C. The reaction was quenched with saturatedaqueous NH₄Cl solution (10 mL) and the mixture allowed to warm to rt.Diethyl ether was added, the layers were separated and the aqueous layerwas further extracted with diethyl ether (4×15 mL). The combined organicextracts were dried over a hydrophobic frit and concentrated in vacuo togive an orange oil. The crude product was loaded in dichloromethane (3mL) and purified on a silica cartridge (25 g) using a gradient of 0-30%cyclohexane/AcOEt over 10 CV. The appropriate fractions were combinedand the solvent evaporated in vacuo to give the product as a white solid(475 mg, 3.00 mmol, 54%).

LCMS (2 min Formic): Rt=0.64 min, [MH]⁺=159.

Intermediate 238: ((3-bromobenzyl)oxy)(tert-butyl)dimethylsilane

To a solution of (3-bromophenyl)methanol (0.321 mL, 2.67 mmol) andimidazole (728 mg, 10.69 mmol) in anhydrous N,N-dimethylformamide (5mL), was added TBDMSCl (484 mg, 3.21 mmol) and the reaction stirred atroom temperature for 1 h. The reaction was diluted with water (50 mL)and extracted with ether (2×50 mL). The organic extracts were thencombined and washed with LiCl (2×20 mL). The extracts were dried over ahydrophobic frit and concentrated in vacuo to give the product((3-bromobenzyl)oxy)(tert-butyl)dimethylsilane (236.9 mg, 0.786 mmol,29%).

LCMS (2 min Formic): Rt=0.63 min, No [MH]⁺ observed.

Intermediate 239:(2S,3R,4R)-1-acetyl-4-((3-(((tert-butyidimethylsilyl)oxy)methyl)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

To a solution of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 100 mg, 0.371 mmol),((3-bromobenzyl)oxy)(tert-butyl)dimethylsilane (for a preparation seeIntermediate 238, 179 mg, 0.594 mmol), DavePhos (29.2 mg, 0.074 mmol)and Pd₂dba₃ (34.0 mg, 0.037 mmol) in 1,4-dioxane (3 mL) was added sodiumtert-butoxide (107 mg, 1.114 mmol) and the reaction mixture degassed.The reaction was then irradiated to 120° C. for 30 min. The reactionmixture was filtered through a 2.5 g Celite column and washed withEtOAc. The filtrate was then concentrated. The sample was loaded indichloromethane onto a silica (10 g) cartridge and purified by flashchromatography eluting with 0-40% ethyl acetate-cyclohexane over 15 CV.The appropriate fractions were combined and concentrated to give(2S,3R,4R)-1-acetyl-4-((3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(66.1 mg, 0.135 mmol, 36%) as an off-white solid. LCMS (2 min Formic):Rt=1.51 min, [MH]⁺=490.

Intermediate 240: 2-bromo-6-(methoxymethyl)pyridine

(6-Bromopyridin-2-yl)methanol (400 mg, 2.127 mmol) was taken up inN,N-dimethylformamide (5 mL) and allowed to stir at 0° C. for 5 min.Sodium hydride (128 mg, 3.19 mmol, 60% suspension in mineral oil) wasthen added, some effervescence occurred and the reaction was allowed tostir at 0° C. for 10 min. Methyl iodide (0.266 mL, 4.25 mmol) was thenadded and the reaction was allowed to warm to rt with stirring over 1 h.The reaction was diluted with water and extracted with EtOAc (×2). Thecombined organics were washed with 10% LiCl(aq), dried using ahydrophobic frit and concentrated to a yellow oil. This oil was purifiedusing a silica column (25 g) and flash chromatography, eluting with0-100% EtOAc:cyclohexane. One major peak was eluted and the appropriatefraction was concentrated and dried to give the product (335 mg, 1.658mmol, 78%) as a colourless oil. LCMS (2 min Formic): Rt=0.78 min,[MH]⁺=202/204.

Intermediate 241: 1-bromo-2-(methoxymethyl)benzene

A solution of (2-bromophenyl)methanol (1 g, 5.35 mmol) inN,N-dimethylformamide (7.5 mL) was cooled to 0° C. and NaH (0.321 g,8.02 mmol, 60% suspension in mineral oil) added portionwise over 10 min.Mel (1.672 mL, 26.7 mmol) was then added and the reaction mixturestirred for 3 h. The reaction mixture was quenched with ammoniumchloride (40 mL) and extracted with EtOAc (2×75 mL). The organic layerswere combined and washed with 10% LiCl (40 mL). The extracts were driedover a hydrophobic frit and concentrated in vacuo to give the product(1.0386 g, 5.17 mmol, 97%) as an orange liquid. LCMS (2 min Formic):Rt=1.10 min, [MNa]⁺=224.

Intermediate 242: methyl2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinate

A solution of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 200 mg, 0.743 mmol), methyl2-fluoronicotinate (0.192 mL, 1.485 mmol) and Et₃N (0.207 mL, 1.485mmol) in N-methyl-2-pyrrolidone (4 mL) was stirred in a closed vessel ina microwave at 200° C. for 75 min. The solution was purified directly byMDAP (HpH). The appropriate fractions were combined and concentrated invacuo to give the product (70 mg, 0.173 mmol, 23%). LCMS (2 min Formic):Rt=1.15 min, [MH]⁺=405.

Intermediate 243:6-(((2S,3S,4R)-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinicacid

To a reaction vessel,(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 1.29 g, 4.79 mmol), and sodiumtert-butoxide (1.841 g, 19.16 mmol) were added in toluene (20 mL). Thesolution was degassed with N₂ and treated with Pd₂(dba)₃ (0.439 g, 0.479mmol), Q-Phos (0.341 g, 0.479 mmol) and ethyl 6-bromopicolinate (1.137mL, 7.18 mmol). The solution was stirred and heated to 60° C. for 16 hunder N₂. LCMS showed that the reaction had proceeded to form thedeacetylated acid. The reaction mixture was filtered through celite anddiluted with water/NaOH(aq) (50:50, 250 mL). This was extracted with DCM(2×200 mL) and the layers separated. The aqueous layer was acidifiedwith 2 M HCl(aq) (150 mL), and extracted with 10% methanol in DCM (3×100mL). The layers were separated and the organics combined and driedthrough a hydrophobic frit before being concentrated in vacuo to givethe crude product (2.116 g) as an orange/white solid. This was taken upin methanol and purified by SPE on an —NH₂ column (20 g), usingsequential solvents (methanol, then 2 M HCl in dioxane). The fractionscontaining product were combined and concentrated in vacuo to give twobatches of the product: Batch 1: an orange/brown solid (331 mg). Batch2: containing product with a substantial impurity (1.5 g) as a redsolid. Batch 2 was taken up in methanol purified by SPE on an —NH₂column (70 g), using sequential solvents (methanol, then 2 M acetic acidin methanol). The fractions containing product were combined andconcentrated in vacuo to give the desired product as an orange/brownsolid (1.218 g).

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=349.

Intermediate 244:6-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinicacid

To a reaction vial,6-(((2S,3S,4R)-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinicacid (for a preparation see Intermediate 243, 1.161 g, 3.33 mmol) wasadded in dichloromethane (50 mL). The reaction was cooled to 0° C.Acetyl chloride (0.948 mL, 13.33 mmol) was added and the reaction leftto stir for 2 h at rt under N₂. Acetyl chloride (0.948 mL, 13.33 mmol)was added and the reaction left to stir at rt for 2 h. Further acetylchloride (1.185 mL, 16.66 mmol) was added and the reaction left to stirat rt for 2 h. Further acetyl chloride (0.5 mL, 7.03 mmol) was added andthe reaction left to stir at 39° C. for 2 h. The reaction was then leftto stir at 40° C. for 16 h. The reaction mixture was concentrated invacuo then re-taken up in DCM:toluene (1:3, 150 mL) and concentrated invacuo (×4) to give the desired product (930 mg) as a brown/white solid.The product was used crude in the next reaction. LCMS (2 min Formic):Rt=0.69 min, [MH]⁺=391.

Intermediate 245: tert-butyl(2-((6-bromopyridin-2-yl)oxy)ethyl)carbamate

A solution of tert-butyl (2-hydroxyethyl)carbamate (0.327 mL, 2.111mmol) in anhydrous THE (10 mL) under nitrogen was cooled in an ice-waterbath and 60% sodium hydride in mineral oil (211 mg, 5.28 mmol) added.The mixture was stirred for 5 min, the ice-bath removed and allowed towarm to rt over 30 min, before a solution of 2,6-dibromopyridine (500mg, 2.111 mmol, commercially available from, for example, Sigma-Aldrich)in anhydrous THE (5 mL) was added. The mixture was stirred undernitrogen at rt for 24 h. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (3×10 mL). The organic extracts werecombined and dried through a hydrophobic frit. The residue was loaded inDCM (4 mL) and purified on a silica cartridge (50 g) using a gradient of0-50% EtOAc in cyclohexane over 10 CV. The appropriate fractions werecombined, the solvent removed in vacuo and the oil dried in a vacuumoven to give the title compound as a white crystalline solid (120 mg,0.378 mmol, 18%).

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=317/319.

Intermediate 246:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((2-nitrophenyl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A solution of 1-fluoro-2-nitrobenzene (0.078 mL, 0.743 mmol),(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 200 mg, 0.743 mmol) and DIPEA(0.220 mL, 1.262 mmol) in dimethyl sulfoxide (1 mL) was added to a flaskand heated to 160° C. in a microwave for 4 h. The reaction mixture waspartitioned between water (20 mL) and Et₂O (20 mL). The layers wereseparated and the aqueous layer further extracted with Et₂O (2×20 mL).The combined organics were back extracted with water (2×20 mL), dried(Na₂SO₄) and concentrated in vacuo. The crude product was taken up inDCM and added to a silica cartridge (25 g) which was purified by flashchromatography, eluting with 0-60% EtOAc/cyclohexane. The appropriatefractions were collected and concentrated in vacuo to afford the desiredproduct as a yellow oil (216 mg, 0.553 mmol, 75%).

LCMS (2 min HpH): Rt=1.19 min, [M−H]⁻=389.

Intermediate 247: 2-(3-bromophenoxy)ethanol

To a mixture of 3-bromophenol (2.0 g, 11.56 mmol) and cesium carbonate(4.71 g, 14.45 mmol) in anhydrous DMF (5 mL) was added 2-bromoethanol(1.632 mL, 23.12 mmol) and the reaction stirred under nitrogen at 50° C.for 20 h. Further 2-bromoethanol (1.632 mL, 23.12 mmol) was added andthe reaction stirred under nitrogen at 50° C. for 8 h. The reactionmixture was allowed to cool to rt and filtered. The filtrate was dilutedwith EtOAc (20 mL) and washed sequentially with 10% aqueous Na₂CO₃ (20mL) and water (20 mL). The organic layer was dried through a hydrophobicfrit and the solvent removed in vacuo. The oil was loaded in DCM (8 mL)and purified on a silica cartridge (100 g) using a gradient of 0-100%EtOAc in cyclohexane over 10 CV. The appropriate fractions were combinedand the solvent removed by rotary evaporation to give the title compoundas a colourless oil (1.10 g, 5.07 mmol, 44%). LCMS (2 min Formic):Rt=0.83 min, no [MH]⁺ observed.

Intermediate 248: (2-(3-bromophenoxy)ethoxy)(tert-butyl)dimethylsilane

To a solution of 2-(3-bromophenoxy)ethanol (for a preparation seeIntermediate 247, 1.10 g, 5.07 mmol) and imidazole (0.690 g, 10.14 mmol)in DCM (8 mL) was added TBDMSCl (0.917 g, 6.08 mmol) and the mixturestirred in a stoppered vessel at room temperature for 2 h. The reactionmixture was filtered and the filtrate washed with water (10 mL). Theorganic layer was dried through a hydrophobic frit and the solventremoved in vacuo. The oil was loaded in DCM (4 mL) and purified on asilica cartridge (50 g) using a gradient of 0-25% EtOAc in cyclohexaneover 10 CV. The appropriate fractions were combined and the solventevaporated in vacuo to give the title compound as a colourless oil (1.37g, 4.13 mmol, 82%).

LCMS (2 min Formic): Rt=1.60 min, no [MH]⁺ observed.

Intermediate 249:(2S,3R,4R)-1-acetyl-4-((3-(2-((tert-butyidimethylsilyl)oxy)ethoxy)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

The title compound was prepared in a similar manner to Intermediate 232from(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231,197 mg, 0.731 mmol) and(2-(3-bromophenoxy)ethoxy)(tert-butyl)dimethylsilane (for a preparationsee Intermediate 248, 363 mg, 1.097 mmol) to give the title compound asa light pink gum (235 mg, 0.452 mmol, 62%). LCMS (2 min Formic): Rt=1.48min, [MH]⁺=520.

Intermediate 250: tert-butyl (2-(3-bromophenoxy)ethyl)carbamate

To a mixture of 3-bromophenol (1.0 g, 5.78 mmol), potassium carbonate(2.4 g, 17.37 mmol) and potassium iodide (1.0 g, 6.02 mmol) in anhydrousDMF (8 mL) was added tert-butyl (2-bromoethyl)carbamate (2.6 g, 11.60mmol) and the reaction mixture stirred under nitrogen for 16 h at 60° C.The reaction was filtered through celite, the filtrate diluted withEtOAc (20 mL) and washed sequentially with NaOH (10 mL, 0.5 M) and water(2×10 mL). The organic layer was dried through a hydrophobic frit andthe filtrate concentrated under reduced pressure. The resulting oil wasloaded in DCM (5 mL) and purified on a silica cartridge (50 g) using agradient of 0-50% EtOAc in cyclohexane over 10 CV. The appropriatefractions were combined and the solvent removed by rotary evaporation togive the title compound as a colourless oil (1.69 g, 5.34 mmol, 92%).

LCMS (2 min Formic): Rt=1.20 min, [MH]⁺=316/318.

Intermediate 251: tert-butyl(2-(3-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenoxy)ethyl)carbamate

The title compound was prepared in a similar manner to Intermediate 232from(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 197 mg, 0.731 mmol) andtert-butyl (2-(3-bromophenoxy)ethyl)carbamate (for a preparation seeIntermediate 250, 347 mg, 1.097 mmol) to give the title compound as alight pink gum (123 mg, 0.244 mmol, 33%). LCMS (2 min Formic): Rt=1.19min, [MH]⁺=505.

Intermediate 252: (2-chloropyrimidin-4-yl)methanol

Methyl 2-chloropyrimidine-4-carboxylate (300 mg, 1.738 mmol) was takenup in dichloromethane (5 mL) and allowed to stir at 0° C. for 5 min.Diisobutylaluminium hydride (3.48 mL, 3.48 mmol, 1 M in THF) was thenadded dropwise and the reaction allowed to warm to rt with stirring over16 h. The reaction was treated with 10% citric acid (aq.) and wasallowed to stir at rt for 30 min. The reaction was then extracted withEtOAc (×2), the combined organics were washed with brine, dried using ahydrophobic frit and concentrated to a yellow solid product (138 mg,0.955 mmol, 55%). This was used crude (˜33% purity) in the nextreaction. LCMS (2 min Formic): Rt=0.39 min, [MH]⁺=145.

Intermediate 253:4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine

(2-Chloropyrimidin-4-yl)methanol (for a preparation see Intermediate252, 135 mg, 0.934 mmol) and imidazole (127 mg, 1.868 mmol) were takenup in N,N-dimethylformamide (5 mL) and treated with TBDMSCl (141 mg,0.934 mmol) and allowed to stir at rt for 2 h. The reaction was dilutedwith water and was extracted with DCM (×2), the combined organics werewashed with 10% LiCl(aq), dried using a hydrophobic frit andconcentrated to a yellow oil. This oil was purified using flash silicachromatography using a silica column (10 g) and eluting with: 0-50%DCM:cyclohexane. One broad peak was eluted and the appropriate fractionswere summed and concentrated to give the product (63 mg, 0.243 mmol,26%) as a colourless oil. LCMS (2 min Formic): Rt=1.38 min, [MH]⁺=259.

Intermediate 254:(2S,3R,4R)-1-acetyl-4-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

The title compound was prepared in a similar manner to intermediate 239from(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 50 mg, 0.186 mmol) and4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (for apreparation see Intermediate 253, 57.7 mg, 0.223 mmol) to give theproduct (30 mg, 0.061 mmol, 33%) as a yellow oil. LCMS (2 min Formic):Rt=1.42 min, [MH]⁺=492.

Intermediate 255: ethyl 6-bromo-3-chloropicolinate

6-Bromo-3-chloropicolinic acid (560 mg, 2.368 mmol) was taken up inethanol (5 mL) and was treated with sulfuric acid (0.126 mL, 2.368 mmol)and allowed to stir at 80° C. for 16 h. The reaction was allowed to coolto rt and was eluted through a NH₂ (5 g) SPE cartridge, washing withMeOH, the eluent was concentrated and dried to give the product (600 mg,2.268 mmol, 96%) as a colourless oil. LCMS (2 min Formic): Rt=1.02 min,[MH]⁺=264/266.

Intermediate 256: (6-bromo-3-chloropyridin-2-yl)methanol

Ethyl 6-bromo-3-chloropicolinate (for a preparation see Intermediate255, 690 mg, 2.61 mmol) was taken up in dichloromethane (5 mL) andallowed to stir at 0° C. for 5 min. Diisobutylaluminium hydride (5.22mL, 5.22 mmol, 1 M in THF) was then added dropwise and the reactionallowed to warm to rt with stirring over 16 h. The reaction was treatedwith further diisobutylaluminium hydride (185 mg, 1.304 mmol, 1 M inTHF) and allowed to stir at rt for 4 h and then to stand at rt for 4days. The reaction was treated with 10% citric acid (aq) and was allowedto stir at rt for 30 min. The reaction was extracted with EtOAc (×2),the combined organics were washed with brine, dried using a hydrophobicfrit and concentrated to a green oil. This oil was purified by flashchromatography using a Si column (10 g) eluting with: 0-50%EtOAc:cyclohexane. One major peak was eluted, the appropriate fractionswere summed and concentrated to give the product (376 mg, 1.690 mmol,65%) as a yellow oil. LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=222/224.

Intermediate 257:6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-chloropyridine

(6-Bromo-3-chloropyridin-2-yl)methanol (for a preparation seeIntermediate 256, 376 mg, 1.690 mmol) and imidazole (230 mg, 3.38 mmol)were taken up in N,N-dimethylformamide (20 mL) and treated with TBDMSCl(280 mg, 1.859 mmol) and allowed to stir at rt for 16 h. The reactionwas diluted with water and was extracted with DCM (×2) the combinedorganics were washed with 10% LiCl (aq), dried using a hydrophobic fritand concentrated to a colourless oil. This oil was purified by flashchromatography (10 g), eluting with 0-25% DCM:cyclohexane. Theappropriate fractions were summed and concentrated to give the product(435 mg, 1.292 mmol, 76%) as a colourless oil. LCMS (2 min Formic):Rt=1.58 min, [MH]⁺=336/338.

Intermediate 258:(2S,3R,4R)-1-acetyl-4-((6-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloropyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

To a solution of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 70 mg, 0.260 mmol) and6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-chloropyridine (for apreparation see Intermediate 257, 140 mg, 0.416 mmol) in 1,4-dioxane(2.5 mL), was added Pd₂(dba)₃ (23.80 mg, 0.026 mmol), sodiumtert-butoxide (74.9 mg, 0.780 mmol) and DavePhos (20.46 mg, 0.052 mmol).The reaction mixture was degassed and irradiated in a microwave to 120°C. for 30 min. The reaction was filtered though a 2.5 g Celite columnand washed with EtOAc. The sample was concentrated and then loaded indichloromethane and purified by flash chromatography on SP4 silica (Si,25 g) using a 10-65% ethyl acetate-cyclohexane over 15 CV. Theappropriate fractions were combined and concentrated to give the product(59.7 mg, 0.114 mmol, 44%) as an off-white solid.

LCMS (2 min Formic): Rt=1.54 min, [MH]⁺=525.

Intermediate 259: (2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

Ethyl 4-aminobenzoate (5.2 g, 31.5 mmol) was taken up in dichloromethane(DCM) (300 mL) under nitrogen. Propionaldehyde (3.41 ml, 47.2 mmol) wasadded and the reaction stirred at room temperature for 90 min. Thereaction was cooled in an ice-bath and (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 6.62 g,34.6 mmol) in DCM (100 mL) added followed by(S)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.545 g, 0.944mmol, 0.182 g, 0.315 mmol) in one portion. The reaction was left to stirin the ice-bath. After 90 min the reaction was diluted with DCM (200 mL)and washed with sat. NaHCO₃ (500 mL). The combined organics were driedwith Na₂SO₄, filtered and concentrated in vacuo to give the product(12.8 g). This was taken up in the minimum of hot EtOAc and thencyclohexane added until precipitation began. Quickly a large amount ofsolid formed. The mixture was reheated until a clear solution formed(additional EtOAc added) then left to cool to rt, then placed in anice-bath. The resulting precipitate was collected by filtration, washedwith cyclohexane (˜100 mL) and dried in the vacuum oven to give theproduct (10.503 g, 25.2 mmol, 80%) as a white solid. Analysis by chiralHPLC was undertaken using a 250×4.6 mm Chiralpak IC column eluting with25% ethanol in heptane at a flow rate of 1 mL/min. Peak 1/minorenantiomer (<0.5%) eluted at 6.3 min, and Peak 2/major enantiomer >99.5%by UV) eluted at 9.2 min. This indicated the product had an ee of >99%.LCMS (2 min HpH): Rt=1.22 min, [MH]⁺=397.

Intermediate 260: (2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of (2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 259, 9.2 g, 23.20 mmol) and pyridine(5.63 ml, 69.6 mmol) in anhydrous dichloromethane (DCM) (800 mL) wascooled in an ice bath under nitrogen, then treated with acetyl chloride(1.980 ml, 27.8 mmol) added drop-wise over 10 min. The mixture wasstirred at 0° C. for 1 h, then allowed to warm to rt and stirred for afurther 3 h. The reaction mixture was transferred to a separating funneland washed with 1M HCl (500 mL), water (500 mL) and saturated sodiumbicarbonate solution (500 mL), dried and evaporated in vacuo to give theproduct (10.2 g, 23.26 mmol, 100%) as a colourless solid.

LCMS (2 min HpH): Rt=1.17 min, [M-NH₂]⁺=439.

Intermediate 261: (2S,3R,4R)-ethyl1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A conical flask was charged with (2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 260, 10 g, 22.80 mmol), ethanol (100mL) and palladium on carbon (0.243 g, 2.280 mmol). The reaction mixturewas stirred under an atmosphere of hydrogen for ˜5 h. The reactionmixture was filtered through celite and eluted with ethanol (2×50 mL).The filtrate was concentrated in vacuo to give a yellow oil (6.918 g,22.73 mmol, 100%). LCMS (2 min Formic): Rt=0.57 min, [M-NH₂]⁺=288.

Intermediate 262: (2S,3R,4R)-ethyl1-acetyl-4-((4-cyano-3-methylphenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

(2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 162 mg, 0.512 mmol),4-bromo-2-methylbenzonitrile (181 mg, 0.922 mmol), Pd₂(dba)₃ (47 mg,0.051 mmol), Q-Phos (38 mg, 0.053 mmol) and Cs₂CO₃ (334 mg, 1.024 mmol)were combined in dry toluene (3 mL). The reaction mixture was de-gassedand then heated at 80° C. under nitrogen for 3 h. The reaction stoppedand cooled to rt and partitioned between ethyl acetate and water. Theorganic layer was separated and aqueous layer further extracted withethyl acetate. The combined organic layers were dried (Na₂SO₄) and conc.to give ˜403 mg of crude orange residue. This was purified bychromatography on SiO₂ (25 g) eluting with 0-50% ethylacetate/cyclohexane over 330 mL to give the product (208 mg, 0.482 mmol,94%) as an orange oil. LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=432.

Intermediate 263: (2S,3R,4R)-ethyl1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of 2-chloro-4-methylpyrimidine (950 mg, 7.39 mmol) andpotassium fluoride (644 mg, 11.09 mmol) and 18-crown-6 (977 mg, 3.70mmol) in dimethyl sulfoxide (DMSO) (14 mL) was heated in a microwave at160° C. for 60 min. Heating was continued for a further 30 min at 160°C. (2S,3R,4R)-ethyl1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 261, 750 mg, 2.464 mmol) in dimethylsulfoxide (DMSO) (3 mL) and DIPEA (2.152 mL, 12.32 mmol) were added andthe vial sealed and heated to 160° C. for 3.5 h. The reaction mixturewas diluted with Et₂O (100 mL), water (100 mL) was added and the layersseparated. The aqueous layer was further extracted with Et₂O (2×60 mL)and the combined organics then back extracted with water (2×60 mL). Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo to afford thecrude product as an orange-brown oil. The crude product was taken up inDCM and added to a silica cartridge (100 g). This was purified by flashchromatography, eluting with 25%-100% EtOAc/cyclohexane. The appropriatefractions were collected and concentrated in vacuo to afford the desiredproduct as a yellow foam (504 mg, 1.271 mmol, 52%).

LCMS (2 min Formic): Rt=0.95 min, [MH]⁺=397.

Intermediate 264:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A round bottom flask was charged with(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 150 mg, 0.557 mmol),2-bromo-5-fluoropyridine (147 mg, 0.835 mmol), sodium tert-butoxide (123mg, 1.281 mmol), toluene (4 mL) and Pd(QPhos)₂ (85 mg, 0.056 mmol). Thereaction mixture was degassed and stirred at 50° C. for 3 h, thereaction mixture was concentrated in vacuo and purified by silica gelcolumn chromatography eluting with a gradient cyclohexane/ethyl acetate(9%-35%) to give title compound as a red gum (188 mg, 83%). LCMS (2 minFormic): Rt=0.98 min, [MH]⁺=365.

Intermediate 265: (2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

Ethyl 4-aminobenzoate (15.6 g, 94 mmol) and acetaldehyde (8.00 ml, 142mmol) were taken up in DCM (300 mL) and allowed to stir at rt for 1 hr.The reaction was then cooled to 0° C. and was treated with (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 19.86 g,104 mmol) and2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.545 g, 0.944mmol), the reaction was allowed to stir at 0° C. for 3 h. The mixturewas diluted with DCM (300 mL), washed with a saturated sodiumbicarbonate solution (600 mL), giving a dense emulsion, from which theorganic layer was separated after half an hour of waiting. The remainingaqueous emulsion was extracted with DCM (200 mL), then diluted withsaturated brine (300 mL) and extracted again with DCM (200 mL). Thismixture was allowed to stand overnight, giving a nice clear organiclayer and aggregation of the emulsion into clumps of white solid in theaqueous layer. The combined organics were dried and evaporated in vacuoto give a colourless solid. The crude product was recrystallised fromEtOAc (300 mL)/cyclohexane to afford the title compound (23.3 g, 60.9mmol, 65%) as a colourless solid. LCMS (2 min HpH): Rt=1.20 min,[MH]⁺=383.

Intermediate 266: (2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of (2S,3S,4R)-ethyl4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 265, 29.5 g, 77 mmol) and pyridine(18.72 mL, 231 mmol) in anhydrous DCM (800 mL) was cooled in an ice bathunder nitrogen, then treated with acetyl chloride (6.58 mL, 93 mmol)added dropwise over 10 min. The mixture was stirred at 0° C. for 1 h,then allowed to warm to room temperature and stirred for a further 3 h.The reaction mixture was transferred to a separating funnel and washedwith 1M HCl (500 mL), water (500 mL) and saturated sodium bicarbonatesolution (500 mL), dried and evaporated in vacuo to give the desiredproduct (33.5 g).

LCMS (2 min HpH): Rt=1.13 min, [MH]⁺=425.

Intermediate 267: (2S,3R,4R)-ethyl1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A conical flask was charged with (2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 266, 9.98 g, 23.51 mmol), ethanol(100 mL) and palladium on carbon (0.250 g, 2.351 mmol). The reactionmixture was stirred under an atmosphere of hydrogen for ˜5 h. Thereaction mixture was filtered through celite and eluted with ethanol(2×50 mL). The filtrate was concentrated in vacuo to give the desiredproduct (6.85 g, 23.59 mmol, 100%) as a yellow oil.

LCMS (2 min Formic): Rt=0.51 min, [M-NH₂]⁺=274.

Intermediate 268:(2S,3R,4R)-1-acetyl-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 267, 718 mg, 2.473 mmol),2-bromo-5-fluoropyridine (653 mg, 3.71 mmol), Pd₂(dba)₃ (226 mg, 0.247mmol), DavePhos(195 mg, 0.495 mmol) and sodium tert-butoxide (713 mg,7.42 mmol) were combined in dry 1,4-dioxane (20 mL) and reaction mixturewas stirred under N₂ at 90° C. The reaction mixture was allowed to stirat 90° C. for 3.5 h. LiOH (118 mg, 4.95 mmol) was added to the reactionmixture in water (4 mL) and reaction mixture continued to heat at 90° C.The reaction mixture was cooled to rt and diluted with ethyl acetate (20mL) and filtered through celite (10 g). The filtrate was concentrated invacuo to give a crude brown solid. This solid was purified by MDAP (TFA)to give the product as a yellow.

LCMS (2 min TFA): Rt=0.58 min, [MH]⁺=358.

Intermediate 269: 2-((tert-butyldimethylsilyl)oxy)-4-chlorobenzonitrile

4-bromo-2-hydroxybenzonitrile (500 mg, 2.53 mmol) and imidazole (344 mg,5.05 mmol) were taken up in N,N-dimethylformamide (DMF) (20 mL) andtreated with TBDMSCl (419 mg, 2.78 mmol) and allowed to stir at rt for16 h. The reaction was diluted with water and was extracted with DCM(×2) the combined organics were washed with 10% LiCl (aq), dried using ahydrophobic frit and concentrated to a colourless oil. This oil waspurified using silica gel column chromatography eluting with a gradientof 0-25% DCM:cyclohexane to give the product (248 mg, 0.794 mmol, 32%)as a colourless oil. LCMS (2 min Formic): Rt=1.52 min, [MH]⁺=No mass-ionseen.

Intermediate 270: (2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

In a RB flask were added (2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 157.4 mg, 0.497 mmol),2-bromopyridine (0.071 mL, 0.746 mmol), sodium tert-butoxide (107.5 mg,1.119 mmol) and Pd(QPhos)₂ (76.6 mg, 0.050 mmol) in toluene (10 mL). Thereaction mixture was stirred under nitrogen at 50° C. for 5.5 h.Pd(QPhos)₂ (38.0 mg, 0.025 mmol) was added and reaction was leftstirring at 50° C. for 20 h. Pd(QPhos)₂ (38.0 mg, 0.025 mmol) was addedand reaction was left stirring at 50° C. for 16 h. The reaction mixturewas partitioned between water and EtOAc. The aqueous phase was extractedwith EtOAc. The organic layers were combined and washed with brine,dried over Na₂SO₄, filtered through a hydrophobic cartridge and thevolatiles were removed under reduce pressure to afford a red gum. Thisgum was purified by silica gel column chromatography eluting with agradient of 0-3% 2M NH₃ in MeOH to give title compound as a red gum (206mg, 0.420 mmol, 84%). LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=394.

Intermediate 271:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 270, 206.7 mg, 0.525 mmol) andlithium hydroxide monohydrate (110 mg, 2.63 mmol) were dissolved intetrahydrofuran (THF) (3 mL) and water (3.00 mL). The reaction wasstirred at rt for 16 h. The reaction mixture was diluted with water andwashed with EtOAc. The aqueous layer was then acidified with 1M HCl(pH=1) and extracted with EtOAc. The organic layers were combined, driedthrough hydrophobic cartridge and the volatiles were removed underreduce pressure to afford the title compound as a red gum (22 mg, 0.061mmol, 12%). LCMS (2 min Formic): Rt=0.60 min, [MH]⁺=366.

Intermediate 272: rac-(2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 200 mg, 0.632 mmol),2-fluoropyrimidine (124 mg, 1.264 mmol) and DIPEA (0.442 mL, 2.53 mmol)in N-methyl-2-pyrrolidone (NMP) (3 mL) was stirred in a closed vesselunder microwave irradiation at 180° C. for 1.5 h. The solution wasdiluted with water and washed with DCM. The combined organic layers wereconcentrated in vacuo. The crude was purified by MDAP (HpH) to give theproduct (142 mg, 0.360 mmol, 57%).

LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=395.

Intermediate 273:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

A solution of rac-(2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 264, 140 mg, 0.355 mmol) and LiOH(25.5 mg, 1.065 mmol) in tetrahydrofuran (THF) (1 mL) and water (1.000mL) was stirred in a closed vessel at rt for 72 h. The solution wasdiluted with 0.5M HCl (3 mL) and washed with DCM (3×5 mL). The organiclayer was dried through a hydrophobic frit to give the product (110 mg,0.300 mmol, 85%). LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=367.

Intermediate 274:(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

The (2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 224, 3 g, 6.66 mmol) and lithiumhydroxide (0.797 g, 33.3 mmol) were taken up in tetrahydrofuran (THF)(20 mL):water (20 mL) and allowed to stir at rt for 2 days. The reactionwas concentrated to remove the THF and was acidified to pH2 with 2N HCl.A white precipitate formed which was removed by filtration and dried togive the product (2.765 g, 6.54 mmol, 98%) as a white solid.

LCMS (2 min Formic): Rt=0.94 min, [MH]⁺=423.

Intermediate 275: benzyl((2S,3R,4R)-1-acetyl-6-carbamoyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 274, 2.76 g, 6.53 mmol) wastaken up in dichloromethane (DCM) (50 mL) and was treated with thionylchloride (2.384 mL, 32.7 mmol) and allowed to stir at rt for 2 h. Thereaction was concentrated and azeotroped with toluene (×2) to give aorange gum, this gum was taken up in acetonitrile (40 mL) and wastreated with DIPEA (3.42 mL, 19.60 mmol) followed by 0.88 ammonia (0.126mL, 6.53 mmol) and was allowed to stir at rt for 30 min. The reactionwas concentrated and purified by silica gel column chromatographyeluting with 0-100% EtOAc:cyclohexane to give the product (2.012 g, 4.77mmol, 73%) as a pale yellow solid. LCMS (2 min Formic): Rt=0.87 min,[MH]⁺=422.

Intermediate 276:(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of benzyl((2S,3R,4R)-1-acetyl-6-carbamoyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 275, 2.02 g, 4.79 mmol) in ethanol(100 mL) was passed through a Thales H-cube flow hydrogenator with a 10%Pd/C CatCart in full H₂ mode at a rate of 1 mL/min. The solvent wasevaporated to afford the product (1.2 g, 4.18 mmol, 87%) as a whitefoam/oil. LCMS (2 min Formic): Rt=0.60 min, [M-NH₂]⁺=271.

Intermediate 277: 2-chloro-4,5-dimethylpyrimidine

To a solution of 2,4-dichloro-5-methylpyrimidine (0.769 ml, 6.13 mmol)in tetrahydrofuran (THF) (34.6 ml)/N-methyl-2-pyrrolidone (NMP) (2.61ml) was added ferric acetylacetonate (0.217 g, 0.613 mmol) and themixture was cooled to 0° C. under nitrogen. Then methylmagnesium bromide(3.2 M in Me-THF) (2.88 ml, 9.20 mmol) was added drop-wise. The mixturewas stirred for 30 min under nitrogen at 0° C. The reaction was thenquenched with saturated aqueous NH₄Cl solution (10 mL). Diethyl etherwas added (10 mL) and the layers were separated. The aqueous layer wasfurther extracted with diethyl ether. The combined organic extracts weredried over a hydrophobic frit and concentrated in vacuo to give anorange oil. This oil was purified by silica gel column chromatographyeluting with cyclohexane/EtOAc 0-30% to give the product (575 mg, 4.03mmol, 66%) as a clear liquid. LCMS (2 min Formic): Rt=0.64 min,[MH]⁺=143.

Intermediate 278: 2-chloro-4-(3,6-dihydro-2H-pyran-4-yl)pyrimidine

A round bottom flask was charged with palladium acetate (111 mg, 0.493mmol), 2-(dicyclohexylphosphino)biphenyl (173 mg, 0.493 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1036 mg, 4.93 mmol), 2,4-dichloropyrimidine (735 mg, 4.93 mmol),potassium fluoride (860 mg, 14.80 mmol) and tetrahydrofuran (THF) (15mL). The solution was stirred at 70° C. under a nitrogen atmosphere for24 h. A saturated solution of NaHCO₃ (10 mL) was added to the mixturewhich was then extracted with diethyl ether (2×15 mL) The organic phasewas dried through a hydrophobic frit and evaporated in vacuo. The samplepurified by column chromatography on silica gel eluting with a 10-50%ethyl acetate-cyclohexane gradient to give the title compound (212.7 mg,22%) as a yellow solid.

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=197.

Intermediate 279:(2S,3S,4R)-2-cyclopropyl-3-methyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A round bottom flask was charged with(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 200 mg, 0.743 mmol),3-bromo-1-methylpyridin-2(1H)-one (209 mg, 1.114 mmol), sodiumtert-butoxide (164 mg, 1.708 mmol), Pd₂(dba)₃ (68.0 mg, 0.074 mmol),QPhos (52.8 mg, 0.074 mmol) and toluene (4 mL). The reaction mixture wasdegassed and stirred under nitrogen for 4 h 20 min. To the reactionmixture Pd₂(dba)₃ (68.0 mg, 0.074 mmol), sodium tert-butoxide (164 mg,1.708 mmol) and QPhos (52.8 mg, 0.074 mmol) were added. The reactionmixture was stirred at 50° C. under nitrogen for 2 h 30 min. Thereaction mixture was concentrated in vacuo and washed with water. Theorganic layer was dried, concentrated in vacuo and purified by silicagel column chromatography eluting with cyclohexane/ethyl acetate(12%-50%) to give title compound (124 mg, 90%) as a cream solid.

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=335.

Intermediate 280:(2S,3S,4R)-2-cyclopropyl-3-methyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To(2S,3S,4R)-2-cyclopropyl-3-methyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 279, 124 mg, 0.371 mmol) in a roundbottom flask hydrogen peroxide (0.319 mL, 3.71 mmol), potassiumcarbonate (102 mg, 0.742 mmol) and dimethyl sulfoxide (DMSO) (4 mL) wereadded. The reaction mixture was stirred at rt for 5 h. To the reactionmixture hydrogen peroxide (0.319 mL, 3.71 mmol) was added. The reactionmixture was stirred overnight at rt, the reaction mixture was dilutedwith DCM and washed with water. The organic layer was dried,concentrated in vacuo and purified by silica gel column chromatographyeluting with DCM/methanol (1.9%-7.6%) to give title compound as a greensolid (15 mg, 77%). LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=353.

Intermediate 281: methyl2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinate

A solution of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 2 g, 7.43 mmol), methyl2-fluoronicotinate (1.850 ml, 14.85 mmol) and NEt₃ (2.070 ml, 14.85mmol) in dimethyl sulfoxide (DMSO) (9.41 ml) was stirred in a closedvessel under microwave irradiation at 160° C. for 1 h. The solution wasdiluted with 0.5M NaOH aqueous solution (30 mL) and washed with DCM(3×30 mL). The organic layers were combined, dried through a hydrophobicfrit and concentrated in vacuo to give crude. This crude was purified bysilica gel column chromatography eluting with a gradient 0-70% ethylacetate in DCM to give the product (950 mg, 2.349 mmol, 32%). LCMS (2min Formic): Rt=1.15 min, [MH]⁺=405.

Intermediate 282:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A solution of methyl2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinate(for a preparation see Intermediate 281, 400 mg, 0.989 mmol), calciumchloride (220 mg, 1.978 mmol) and NaBH₄ (748 mg, 19.78 mmol) intetrahydrofuran (THF) (5 mL) and ethanol (2.5 mL) was stirred undernitrogen at 65° C. for 1 h. The reaction mixture was concentrated invacuo and washed between ethyl acetate and water. The organic layer wasfurther washed with water and concentrated in vacuo to give crudeproduct. The crude was purified by MDAP (HpH) to give the product (89mg, 0.236 mmol, 24%).

LCMS (2 min Formic): Rt=0.61 min, [MH]⁺=377.

Intermediate 283:3-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-6-methylpyridine

The (2-chloro-6-methylpyridin-3-yl)methanol (500 mg, 3.17 mmol) wastaken up in N,N-dimethylformamide (DMF) (5 mL) and treated withimidazole (432 mg, 6.35 mmol) and TBDMSCl (478 mg, 3.17 mmol) andallowed to stir at rt for 16 h. The reaction was treated with furtherTBDMSCl (239 mg, 1.586 mmol) and allowed to stir at rt for 5 h. Thereaction was diluted with water and extracted with DCM (×2) the combinedorganics were washed with 10% LiCl (aq), dried using a hydrophobic fritand concentrated to a gum. This gum was purified using a columnchromatography, elute: 0-50% DCM:cyclohexane, one broad peak was eluted,the appropriate fractions were summed and concentrated to give theproduct (754 mg, 2.77 mmol, 87%) as a colourless oil.

LCMS (2 min Formic): Rt=1.53 min, [MH]⁺=272.

Intermediate 284:(2S,3R,4R)-1-acetyl-4-((3-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

The(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 100 mg, 0.371 mmol),3-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-6-methylpyridine (fora preparation see Intermediate 283, 121 mg, 0.446 mmol), sodiumtert-butoxide (107 mg, 1.114 mmol), Pd₂(dba)₃ (34.0 mg, 0.037 mmol),DavePhos (29.2 mg, 0.074 mmol) and 1,4-dioxane (2 mL) were placed in amicrowaveable vial and irradiated in a microwave at 120° C. for 30 min.The reaction was filtered through celite, washing with EtOAc, the eluentwas concentrated to a brown gum. This gum was purified using a columnchromatography, elute: 0-50% EtOAc:cyclohexane, one major peak waseluted and the appropriate fractions were summed and concentrated togive the product (33 mg, 0.065 mmol, 18%) as a yellow gum. LCMS (2 minFormic): Rt=1.31 min, [MH]⁺=505.

Intermediate 285:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)-6-methylpyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

The(2S,3R,4R)-1-acetyl-4-((3-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 284, 53 mg, 0.105 mmol) was taken upin 1M TBAF/THF (1 ml, 1.00 mmol) and allowed to stir at rt for 1 h. Thereaction was concentrated and purified using a column chromatography,elute: 0-10% 2M NH₃/MeOH:DCM, one major peak was eluted, the appropriatefractions were summed and concentrated to give the product (75 mg, 0.192mmol) as brown solid. This was not pure but carried through as was tothe next step. LCMS (2 min Formic): Rt=0.67 min, [MH]⁺=391.

Intermediate 286: benzyl((2S,3R,4R)-6-cyano-2-cyclopropyl-1-isobutyryl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a suspension of benzyl((2S,3S,4R)-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 229, 200 mg, 0.553 mmol) and DIPEA(0.145 mL, 0.830 mmol) in dichloromethane (DCM) (5 mL), was addedisobutyryl chloride (0.087 mL, 0.830 mmol) and the reaction allowed tostir under nitrogen for 1 h. A further portion of isobutyryl chloride(0.087 mL, 0.830 mmol) in dichloromethane (DCM) (5 mL) was added and thereaction allowed to stir for 16 h. Further isobutyryl chloride (0.580mL, 5.53 mmol) and acetonitrile (5.00 mL) were added and the reactionheated to 50° C. for 1 h. The reaction was allowed to cool to rt andpartitioned between NaHCO₃ and DCM. The organic layer was removed andthe aqueous layer re-extracted with DCM. The organic extracts werecombined and washed with water, dried over a hydrophobic frit andconcentrated in vacuo. The sample was purified by silica gel columnchromatography eluting with a 5-25% ethyl acetate-cyclohexane gradientto give the product (92.1 mg, 0.213 mmol, 39%) as a pale yellow oil.LCMS (2 min Formic): Rt=1.19 min, [MH]⁺=432.

Intermediate 287:(2S,3R,4R)-4-amino-2-cyclopropyl-1-isobutyryl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

To a solution of benzyl((2S,3R,4R)-6-cyano-2-cyclopropyl-1-isobutyryl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 286, 92 mg, 0.213 mmol) intetrahydrofuran (THF) (1.36 mL), was added TBAF (1M in THF) (0.640 mL,0.640 mmol) and the reaction allowed to stir under nitrogen at 60° C.for 26 h. The reaction mixture was concentrated and then partitionedbetween 1M HCl and DCM and the aqueous layer was re-extracted with DCM.The aqueous layer was basified with NaHCO₃ and extracted with DCM twice.These two organic layers were combined and concentrated. The residue waspurified by silica gel column chromatography eluting with a 20-100%ethyl acetate-cyclohexane gradient to give the product (38.9 mg, 0.131mmol, 61%) as a an off-white solid. LCMS (2 min Formic): Rt=0.65 min,[MH]⁺=298.

Intermediate 288:(2S,3R,4R)-2-cyclopropyl-1-isobutyryl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile

To a solution of(2S,3R,4R)-4-amino-2-cyclopropyl-1-isobutyryl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 287, 38.7 mg, 0.130 mmol) indimethyl sulfoxide (DMSO) (3 mL), was added 18-crown-6 (17.20 mg, 0.065mmol), potassium fluoride (11.34 mg, 0.195 mmol) and DIPEA (0.039 mL,0.221 mmol) and the reaction irradiated to 140° C. for 6 h. A furtherportion of 2-chloro-4-methylpyrimidine (18.40 mg, 0.143 mmol),18-crown-6 (17.20 mg, 0.065 mmol), potassium fluoride (11.34 mg, 0.195mmol) and DIPEA (0.039 mL, 0.221 mmol) were added and the reactionirradiated to 160° C. for 4 h. The reaction mixture was diluted withwater and extracted twice with EtOAc. The organic extracts werecombined, washed with brine, dried over a hydrophobic frit andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with a gradient of 0-20% Methanol-DCM. Theresidue was further purified by MDAP (Formic) to give the product (5 mg,0.013 mmol, 10%) as an off-white solid.

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=390.

Intermediate 289: (2S,3R,4R)-ethyl1-acetyl-4-((5-cyanothiophen-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A mixture of (2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 303 mg, 0.957 mmol),5-bromothiophene-2-carbonitrile (150 mg, 0.798 mmol), cesium carbonate(520 mg, 1.595 mmol), Pd-PEPPSI-IPent (43.4 mg, 0.064 mmol) in1,2-dimethoxyethane (DME) (10 mL) was put in a microwave vessel. Thevessel was sealed and heated in microwave at 120° C. for 3 h. Themixture was dissolved in ethyl acetate (10 mL) and washed through acelite cartridge (10 g). The washing was evaporated and purified by MDAP(Formic) to give the title compound (31.9 mg, 9%) as a yellow solid.

LCMS (2 min HpH): Rt=1.16 min, [MH]⁺=424.

Intermediate 290:(2S,3R,4R)-1-acetyl-4-((5-cyanothiophen-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

A solution of lithium hydroxide (9.02 mg, 0.377 mmol) in water (1.0 mL)was added to a solution of (2S,3R,4R)-ethyl1-acetyl-4-((5-cyanothiophen-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 289, 31.9 mg, 0.075 mmol) intetrahydrofuran (THF) (1 mL) and the mixture was stirred at RT in asealed round-bottom flask for 5 h. HCl (0.5M) (0.753 mL, 0.377 mmol) wasadded to the reaction mixture followed by water (5 mL). The mixture wasextracted with 10% MeOH/DCM (3×5 mL), the organic phase was driedthrough a hydrophobic frit and evaporated in vacuo to give titlecompound (21.1 mg, 71%) as a green oil.

LCMS (2 min HpH): Rt=0.68 min, [MH]⁺=396.

Intermediate 291:(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

The (2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 266, 2 g, 4.71 mmol) and lithiumhydroxide (0.564 g, 23.56 mmol) were taken up in THE (20 mL):water (20mL) and allowed to stir at rt for 16 h. The reaction was acidified topH2 with 2N HCl, a white precipitate formed which was removed byfiltration and dried to give the desired product (1.851 g, 4.67 mmol,99%) as a white solid. LCMS (2 min Formic): Rt=0.87 min, [MH]⁺=397.

Intermediate 292:(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 260, 2 g, 4.56 mmol) and lithiumhydroxide (0.546 g, 22.80 mmol) was taken up in THE (20 mL):Water (20mL) and allowed to stir at rt for 16 h. The reaction was acidified topH2 with 2N HCl and was extracted into EtOAc. The organic phase wasdried using a hydrophobic frit and concentrated to give the desiredproduct (1.89 g, 4.6 mmol) as a white solid. LCMS (2 min Formic):Rt=0.92 min, [MH]⁺=411.

Intermediate 293: 2-((tert-butyldimethylsilyl)oxy)ethanamine

To a stirred solution of ethanolamine (1.980 mL, 32.7 mmol), DMAP (0.040g, 0.327 mmol) and triethylamine (6.85 mL, 49.1 mmol) in DCM (50 mL) wasadded TBDMSCl (5.68 g, 37.7 mmol). The reaction was allowed to stir atrt for 16 h. The reaction was quenched with NH₄Cl_((aq)) and extractedwith DCM, the organic phase was washed with water, dried using ahydrophobic frit and concentrated and dried to give the product (3.607g, 20.57 mmol, 63%) as a yellow oil.

LCMS (2 min Formic): Not observed.

Intermediate 294: benzyl((2S,3R,4R)-1-acetyl-6-((2-((tert-butyldimethylsilyl)oxy)ethyl)carbamoyl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The(2S,3R,4R)-1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 292, 1.89 g, 4.60 mmol) wastaken up in DCM (50 mL) and was treated with thionyl chloride (1.680 mL,23.02 mmol) and allowed to stir at rt for 2 h. The reaction wasconcentrated and azeotroped with toluene (×2) to give a orange gum, thisgum was taken up in acetonitrile (40 mL) and was treated with DIPEA(2.413 mL, 13.81 mmol) followed by2-((tert-butyldimethylsilyl)oxy)ethanamine (1.050 g, 5.99 mmol) and wasallowed to stir at rt for 1 h. The reaction was concentrated andpurified using a 25 g Si column eluting with 0-50% EtOAc:cyclohexane,the appropriate fractions were summed and concentrated to give thedesired product (2.383 g, 4.20 mmol, 91%) as a yellow solid.

LCMS (2 min Formic): Rt=1.30 min, [MH]⁺=568.

The following intermediates were prepared in a similar manner toIntermediate 294 using thionyl chloride to couple Intermediate 274(2-cPr) or 291 (2-Me) with Intermediate 293.

Rt (mins) Int Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)295 benzyl ((2S,3R,4R)-1- acetyl-6-((2-((tert- butyldimethylsilyl)oxy)ethyl)carbamoyl)-2- cyclopropyl-3-methyl- 1,2,3,4- tetrahydroquinolin-4-yl)carbamate

944 79 580 1.32 (2 min Formic) 296 benzyl ((2S,3R,4R)-1-acetyl-6-((2-((tert- butyldimethylsilyl)oxy) ethyl)carbamoyl)-2,3-dimethyl-1,2,3,4- tetrahydroquinolin-4- yl)carbamate

2057 80 554 1.27 (2 min Formic)

Intermediate 297:(2S,3R,4R)-1-acetyl-4-amino-N-(2-((tert-butyidimethylsilyl)oxy)ethyl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

Benzyl((2S,3R,4R)-1-acetyl-6-((2-((tert-butyldimethylsilyl)oxy)ethyl)carbamoyl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 294, 2.383 g, 4.20 mmol) was takenup in ethanol (30 mL) and was treated with 10% Pd/C (200 mg, 1.879 mmol)and allowed to stir at rt under a atmosphere of hydrogen for 16 h, Thereaction was filtered through celite, concentrated and dried to give thedesired product (1.350 g, 3.11 mmol, 96%) as an off-white solid. LCMS (2min Formic): Rt=0.90 min [MH]⁺=434.

The following intermediates were prepared in a similar manner toIntermediate 297 using 10% Pd/C—H₂ to deprotect Intermediate 295 (2-cPr)or 296 (2-Me).

Rt (mins) Int. Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺method) 298 (2S,3R,4R)-1-acetyl-4- amino-N-(2-((tert-butyldimethylsilyl) oxy)ethyl)-2- cyclopropyl-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

685 94 446 0.89 (2 min Formic) 299 (2S,3R,4R)-1-acetyl-4-amino-N-(2-((tert- butyldimethylsilyl) oxy)ethyl)-2,3-dimethyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

1126 95 420 0.86 (2 min Formic)

Intermediate 300:(2S,3R,4R)-1-acetyl-N-(2-((tert-butyidimethylsilyl)oxy)ethyl)-2-ethyl-4-((5-fluoro-4-methylpyrimidin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel(2S,3R,4R)-1-acetyl-4-amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 297,100 mg, 0.231 mmol), sodiumtert-butoxide (89 mg, 0.922 mmol), Pd₂(dba)₃ (31.7 mg, 0.035 mmol),DavePhos (27.2 mg, 0.069 mmol) and 2-chloro-5-fluoro-4-methylpyrimidine(50.7 mg, 0.346 mmol) were added in 1,4-dioxane (6 mL). The solution wasdegassed with N₂ and left to stir at 100° C. under N₂ for 2 h. Pd₂(dba)₃(32 mg, 0.035 mmol) and DavePhos (28 mg, 0.071 mmol) were added and thereaction left to stir at 100° C. under N₂ for 1 h.2-Chloro-5-fluoro-4-methylpyrimidine (50.7 mg, 0.346 mmol), Pd₂(dba)₃(32 mg, 0.035 mmol) and DavePhos (28 mg, 0.071 mmol) were added and thereaction left to stir at 100° C. under N₂ for 1 h. The reaction was leftto stir at 100° C. for a further 16 h. The reaction was left to cool tort and filtered through celite. The celite was washed with ethyl acetate(20 mL) and the combined filtrates washed with sat. aq. brine solution(2×30 mL). The layers were separated, the organic phase was driedthrough a hydrophobic frit and concentrated in vacuo to give 340 mg ofcrude product as a brown gum. This was purified by chromatography onSiO₂ (25 g, eluting with 0-100% ethyl acetate/cyclohexane). Thefractions containing product were combined and concentrated in vacuo togive 37 mg of product as an orange solid.

LCMS (2 min Formic): Rt=1.27 min [MH]⁺=544.

The following intermediates were prepared in a similar manner toIntermediate 300 using Pd₂(dba)₃, DavePhos and NaOtBu to couple theappropriate aryl halide with Intermediate 297 (2-Et), 298 (2-cPr) or 299(2-Me).

Rt (mins) Int. Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺method) 301 (2S,3R,4R)-1-acetyl-N- (2-((tert- butyldimethylsilyl)oxy)ethyl)-2-cyclopropyl-4- ((5-fluoro-4- methylpyrimidin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6- carboxamide

25 20 556 1.29 (2 min Formic) 302 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-4-((5-fluoro-4- methylpyrimidin-2-yl)amino)-2,3-dimethyl- 1,2,3,4- tetrahydroquinoline-6- carboxamide

20 16 530 1.23 (2 min Formic) 303 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-2-ethyl-4-((5- fluoro-6-methylpyridin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6- carboxamide

131 84 543 1.23 (2 min Formic) 304 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-2-cyclopropyl-4- ((5-fluoro-6-methylpyridin-2- yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide

25 40 555 1.27 (2 min Formic) 305 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-4-((5-fluoro-6- methylpyridin-2-yl)amino)-2,3-dimethyl- 1,2,3,4- tetrahydroquinoline-6- carboxamide

36 29 529 1.18 (2 min Formic) 306 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-2-ethyl-3-methyl- 4-((4-methylpyridin-2-yl)amino)-1,2,3,4- tetrahydroquinoline-6- carboxamide

66 55 525 1.00 (2 min Formic) 307 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-2-cyclopropyl-3- methyl-4-((4-methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6- carboxamide

39 32 537 1.00 (2 min Formic) 308 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-2,3-dimethyl-4- ((4-methylpyridin-2-yl)amino)-1,2,3,4- tetrahydroquinoline-6- carboxamide

66 54 511 0.97 (2 min Formic) 309 (2S,3R,4R)-1-acetyl-N- (2-((tert-butyldimethylsilyl)oxy) ethyl)-4-((4-cyano-2- fluorophenyl)amino)-2-cyclopropyl-3-methyl- 1,2,3,4- tetrahydroquinoline-6- carboxamide

36 14 565 1.32 (2 min Formic)

Intermediate 310:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(rac-2-hydroxypropyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 70 mg, 0.184 mmol) and HATU (84mg, 0.221 mmol) in DMF (2 mL) was added 1-aminopropan-2-ol (0.017 mL,0.221 mmol) and DIPEA (0.129 mL, 0.738 mmol). The reaction mixture wasstirred at rt for 1 h. The reaction mixture was partitioned betweenether 25 mL and water 50 mL and the aqueous extracted with ether (3×25mL). The combined organics were washed with saturated brine (10 mL),dried over magnesium sulphate and evaporated in vacuo to afford thedesired product (50 mg, 0.103 mmol, 56%) as a yellow oil. LCMS (2 minHpH): Rt=0.87 min, [MH]⁺=437.

Intermediate 311: benzyl((2S,3S,4R)-6-(ethylcarbamoyl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

4-Amino-N-ethylbenzamide (550 mg, 3.35 mmol) and acetaldehyde (0.284 mL,5.02 mmol) were taken up in dichloromethane (DCM) (50 mL) and allowed tostir at rt for 1 h. The reaction was then cooled to 0° C. and wastreated with (E)-benzyl prop-1-en-1-ylcarbamate (for a preparation seeIntermediate 1, 705 mg, 3.68 mmol) and2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 19.34 mg, 0.033mmol) the reaction was allowed to stir at 0° C. for 16 h, a precipitateresulted. The precipitate was removed by filtration and dried to givethe product (981 mg, 2.57 mmol, 77%) as a white solid. Analysis bychiral HPLC was undertaken using a 250×4.6 mm Chiralcel OD-H columneluting with 15% ethanol in heptane at a flow rate of 1 mL/min. Peak1/major enantiomer (96% by UV) eluted at 10.2 min, and Peak 2/minorenantiomer (4% by UV) eluted at 13.4 min. This indicated the product hadan ee of 92%. LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=382.

Intermediate 312: benzyl((2S,3R,4R)-1-acetyl-6-(ethylcarbamoyl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Benzyl((2S,3S,4R)-6-(ethylcarbamoyl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 311, 500 mg, 1.311 mmol) was treatedwith acetic anhydride (5 ml, 53.0 mmol) and allowed to stir at 140° C.for 1 h, The reaction was diluted with EtOAc and was washed with 1N NaOH(aq) and was dried using a hydrophobic frit to give a yellow solid. Thissolid was purified using a 25 g Si column eluting with 0-100%EtOAc:cyclohexane, the appropriate fractions were summed, concentratedand dried to give the product (395 mg, 0.933 mmol, 71%) as a buff solid.LCMS (2 min Formic): Rt=0.89 min, [MH]⁺=424.

Intermediate 313:(2S,3R,4R)-1-acetyl-4-amino-N-ethyl-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

Benzyl((2S,3R,4R)-1-acetyl-6-(ethylcarbamoyl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 312, 395 mg, 0.933 mmol) was takenup in Ethanol (10 mL) and the reaction was hydrogenated using the H-cube(settings: 25° C., 1 bar, 1 ml/min flow rate) and 10% Pd/C CatCart 30 asthe catalyst. The reaction was concentrated and dried to give theproduct (255 mg, 0.881 mmol, 94%) as a white solid.

LCMS (2 min Formic): Rt=0.43 min, [MH]⁺=290.

Intermediate 314: (2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of (2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 300 mg, 0.948 mmol),4-chloro-2-methylpyrimidine (244 mg, 1.896 mmol) and DIPEA (0.331 mL,1.896 mmol) in N-methyl-2-pyrrolidone (NMP) (10 mL) was heated in amicrowave in a sealed vessel at 200° C. for 3.5 h. The solution wasdiluted with ethyl acetate (30 mL) and washed with water (2×20 mL). Theorganic layer was washed through a hydrophobic frit and concentrated invacuo. It appeared that NMP was still present so the solution wasdiluted with ethyl acetate (20 mL) and washed again with water (2×20mL). The solvent was evaporated in vacuo to give 350 mg crude as anorange gum. The crude was dissolved in DCM and loaded to a 50 g silicaflash cartridge and purified over a gradient of 0-50% ethyl acetate incyclohexane over 12 CVs. The appropriate fractions were combined andconcentrated in vacuo to give the product (150 mg, 0.367 mmol, 39%).

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=409.

Intermediate 315:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

A solution of (2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 314, 60 mg, 0.147 mmol) and LiOH(10.55 mg, 0.441 mmol) in tetrahydrofuran (THF) (1 mL) and Water (1.0mL) was stirred in a closed vessel at room temp for 16 h. The reactionmixture was concentrated in vacuo, diluted with DCM and washed withwater. The aqueous layer was acidified to pH 1 and washed with DCM. Theproduct remained in the aqueous layer. The layers were combined andconcentrated in vacuo. The crude was then dissolved in 1:1 MeOH:DMSO (1mL) and purified by MDAP (Formic). The appropriate fractions werecombined and concentrated in vacuo to give the product (37 mg, 0.097mmol, 66%). LCMS (2 min Formic): Rt=0.58 min, [MH]⁺=381.

Intermediate 316:(2S,3R,4R)-1-acetyl-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-ethyl-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a microwave vial(2S,3R,4R)-1-acetyl-4-amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 297, 100 mg, 0.231 mmol),4-chloro-2-methylpyrimidine (59.3 mg, 0.461 mmol), and DIPEA (0.121 mL,0.692 mmol) were added and the reaction heated to 200° C. in a microwavefor 30 min. The reaction vessel was sealed and heated to 200° C. in amicrowave for a further 1 h. The reaction vessel was sealed and heatedto 200° C. in a microwave for a further 1 h. The reaction vessel wassealed and heated to 200° C. in a microwave for a further 1 h. Thereaction was partitioned between water (10 mL) and diethyl ether (15mL). The layers were separated and the aqueous layer was extracted withdiethyl ether (15 mL) a further two times. The reaction mixture wasconcentrated in vacuo to give the crude product as an orange oil. Thiswas purified by chromatography on SiO₂ (10 g, eluting with 0-40% ethylacetate/cyclohexane) the product was found to have stayed on the columnso it was eluted again with 40-100% ethyl acetate cyclohexane. Theproduct was found to have stayed on the column, it was eluted again with0-20% methanol DCM. The fractions containing product were combined andconcentrated in vacuo to give the product (35 mg, 0.067 mmol, 29%) as anorange solid. LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=526.

Intermediate 317: (2S,3R,4R)-ethyl1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of 2-chloro-4-methylpyrimidine (950 mg, 7.39 mmol), potassiumfluoride (644 mg, 11.09 mmol) and 18-crown-6 (977 mg, 3.70 mmol) in DMSO(15 mL) was heated in a microwave at 180° C. for 90 min.(2S,3R,4R)-ethyl1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 261, 750 mg, 2.464 mmol) in DMSO (4mL) and DIPEA (2.152 mL, 12.32 mmol) were added and the vial sealed andheated to 160° C. for 2 h. The reaction was then heated to 160° C. foran additional 1.5 h. The reaction mixture was diluted with Et₂O (100mL), water (100 mL) was added and the layers separated. The aqueouslayer was further extracted with Et₂O (2×60 mL) and the combinedorganics then back extracted with water (2×60 mL). The organic layer wasdried (Na₂SO₄) and concentrated in vacuo to afford the crude product asan orange-brown oil. The crude product was taken up in DCM and added toa silica cartridge (100 g). This was purified by flash SP4chromatography, eluting with 30-100% EtOAc/cyclohexane. The appropriatefractions were collected and concentrated in vacuo to afford the desiredproduct as a yellow foam (439 mg, 1.107 mmol, 45%). LCMS (2 min Formic):Rt=0.94 min, [MH]⁺=397.

Intermediate 318:(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 317, 439 mg, 1.107 mmol) was takenup in THE (5 mL) and water (5.00 mL). lithium hydroxide (66.3 mg, 2.77mmol) was added and the reaction stirred for ˜1 h at rt. Stirring wascontinued for a further 1 h. 2M HCl(aq) (1.384 mL, 2.77 mmol) was addedfollowed by 10% MeOH/DCM (40 mL) and water (30 mL). The biphasic mixturewas stirred for 5 min and the layers then separated. The aqueous layerwas further extracted with 10% MeOH/DCM (2×30 mL). After three washesthe aqueous layer was analysed and found to contain a trace of product,therefore the aqueous was further extracted with 10% MeOH/DCM (20 mL)and DCM (2×20 mL). The combined organics were collected, dried (Na₂SO₄)and concentrated in vacuo to afford the desired product as a yellowsolid (375.2 mg, 1.018 mmol, 92%).

LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=369.

Intermediate 319: (2S,3R,4R)-ethyl1-cetyl-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

Two identical reactions set up in series to run one after the other onthe same scale, each vial set up as follows: 2-chloro-4-methylpyrimidine(996 mg, 7.75 mmol), potassium fluoride (675 mg, 11.62 mmol) and18-crown-6 (1024 mg, 3.87 mmol) were added to a 10-20 mL microwave vial.(2S,3R,4R)-ethyl1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 261, 730 mg, 2.51 mmol) in dimethylsulfoxide (DMSO) (17 mL) and DIPEA (2.255 mL, 12.91 mmol) were added andthe vial sealed and heated to 160° C. for 4 h. The vials were combinedand the reaction mixture was diluted with Et₂O (100 mL), water (100 mL)was added and the layers separated. The aqueous layer was furtherextracted with Et₂O (2×100 mL) and the combined organics then backextracted with water (2×60 mL). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as an orange-oil. Thecrude product was taken up in DCM and added to a silica cartridge (100g). This was purified by flash chromatography, eluting with 25%-100%EtOAc/cyclohexane. The product was recolumned by flash chromatography,eluting with 25%-100% EtOAc/cyclohexane. The appropriate fractions werecollected and concentrated in vacuo to afford the desired product as anorange foam (861 mg, 2.251 mmol, 45%). LCMS (2 min Formic): Rt=0.88 min,[MH]⁺=383.

Intermediate 320:(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 319, 861 mg, 2.251 mmol) was takenup in THE (9.7 mL) and Water (9.70 mL). lithium hydroxide (135 mg, 5.63mmol) was added and the reaction stirred for ˜1 h at RT. Stirring wascontinued for a further 1 h. 2M HCl_((aq)) (2.81 mL, 5.63 mmol) wasadded followed by 10% MeOH/DCM (40 mL) and water (30 mL). The biphasicmixture was stirred for 5 min and the layers then separated. The aqueouslayer was further extracted with 10% MeOH/DCM (3×30 mL) and DCM (30 mL).The combined organics were collected, dried (Na₂SO₄) and concentrated invacuo to afford the desired product as a yellow solid (824 mg, 2.093mmol, 93%). LCMS (2 min Formic): Rt=0.64 min, [MH]⁺=355.

Intermediate 321:(2S,3R,4R)-1-acetyl-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid TFA salt

(2S,3R,4R)-ethyl1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(718 mg, 2.473 mmol), 2-bromo-5-fluoropyridine (653 mg, 3.71 mmol),Pd₂(dba)₃ (226 mg, 0.247 mmol), DavePhos (195 mg, 0.495 mmol) and sodiumtert-butoxide (713 mg, 7.42 mmol) were combined in dry 1,4-dioxane (20mL) and reaction mixture was stirred under N₂ at 90° C. for 3.5 h. LiOH(118 mg, 4.95 mmol) was added to the reaction mixture in water (4 mL)and reaction mixture continued to heat at 90° C. for a further 2 h.Reaction mixture was cooled to rt and diluted with ethyl acetate (20 mL)and filtered through celite (10 g). The filtrate was conc. in vacuo togive ˜980 mg crude brown solid. This was purified by 4× large scale MDAP(TFA). The fractions containing desired product concentrated in vacuo togive the product (119 mg, 0.252 mmol, 10%) as a yellow solid.

LCMS (2 min TFA): Rt=0.58 min, [MH]⁺=358.

Intermediate 322: (2S,3R,4R)-ethyl1-acetyl-2,3-dimethyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of (2S,3R,4R)-ethyl1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 267, 500 mg, 1.722 mmol),2-fluoropyrimidine (203 mg, 2.066 mmol) and DIPEA (0.602 mL, 3.44 mmol)in anhydrous dimethyl sulfoxide (DMSO) (2.5 mL) was heated at 140° C.for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washedwith water (2×50 mL) and brine (2×50 mL) before being dried through ahydrophobic frit. The filtrate was evaporated to leave the crudeproduct. Purification was undertaken by flash column chromatography. Thecrude material was loaded onto a 50 g silica column and eluted using agraduating solvent system of 0-100% ethyl acetate in cyclohexane.Combination and evaporation of the desired fractions gave the product asa yellow oil (620 mg, 1.683 mmol, 98%).

LCMS (2 min Formic): Rt=0.87 min, [MH]⁺=369.

Intermediate 323:(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-2,3-dimethyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 322, 620 mg, 1.683 mmol) was takenup in tetrahydrofuran (THF) (4 mL) and water (4.00 mL). Lithiumhydroxide (101 mg, 4.21 mmol) was added and the reaction stirred for atrt overnight. 2M HCl(aq) (2 mL, 4.00 mmol) was added followed by 10%MeOH/DCM (30 mL) and water (30 mL). The biphasic mixture was stirred for5 min and the layers then separated. The aqueous layer was furtherextracted with 10% MeOH/DCM (2×200 mL) and the combined organics weredried through a hydrophobic frit and concentrated to leave the productas a pale yellow foam (160 mg, 0.47 mmol, 28%). The aqueous layer wasconcentrated and the residue was dissolved in MeOH (˜10 mL), dried(MgSO4), filtered and concentrated to leave further product as a yellowsolid (300 mg, 0.88 mmol, 52%).

LCMS (2 min Formic): Rt=0.63 min, [MH]⁺=341.

Intermediate 324: (2S,3R,4R)-ethyl1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

(2S,3R,4R)-Ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 800 mg, 2.53 mmol),4-bromobenzonitrile (828 mg, 4.55 mmol), Pd₂(dba)₃ (232 mg, 0.253 mmol),Pd(Q-Phos) (180 mg, 0.253 mmol) and Cs₂CO₃ (1.6 g, 4.91 mmol) werecombined in dry toluene (12 mL). The reaction mixture was de-gassed andthen heated at 80° C. under N₂. After 4 h further portions of Pd₂(dba)₃(232 mg, 0.253 mmol), Pd (Q-Phos) (180 mg, 0.253 mmol) and Cs₂CO₃ (1.6g, 4.91 mmol) were added and the reaction mixture and heating wascontinued at 80° C. under N₂. The reaction mixture left to heat at 80°C. overnight under N₂. The reaction mixture cooled to rt and partitionedbetween ethyl acetate and water. The organic layer was separated andaqueous layer further extracted with ethyl acetate. The combined organiclayers were dried (Na₂SO₄) and concentrated to give ˜2.3 g of crudeorange residue. This was purified by chromatography on SiO₂ (100 gcartridge, eluting with 0-50% ethyl acetate/cyclohexane over 1320 mL) togive 615 mg of dark orange foamy solid product.

LCMS (2 min Formic): Rt=1.12 min, [M−H]⁻=416.

Intermediate 325:(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 324, 599 mg, 1.435 mmol) wasdissolved in 1,4-dioxane (4 mL). Water (4.0 mL) was added followed byLiOH (68.7 mg, 2.87 mmol) and reaction the mixture was stirred at rt.After 3.5 h the dioxane was removed in vacuo and acetic acid (0.164 mL,2.87 mmol) was added. The reaction mixture was partitioned between DCMand water. The organic layer was separated and the aqueous layerextracted with DCM (3×30 mL). The combined organic layers were dried(Na₂SO₄) and concentrated to give the product (536 mg, 1.376 mmol, 96%)as a red solid. LCMS (2 min Formic): Rt=0.92 min, [M-NHAr]⁺=272.

Intermediate 326: tert-butyl(2-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamido)ethyl)carbamate

(2S,3R,4R)-1-Acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 325, 100 mg, 0.257 mmol) wasdissolved in N,N-dimethylformamide (DMF) (2 mL) and HATU (146 mg, 0.385mmol) was added followed by tert-butyl (2-aminoethyl)carbamate (0.051mL, 0.325 mmol) and DIPEA (0.135 mL, 0.770 mmol). The reaction mixturestirred under N₂ at rt for 4 h. Reaction mixture was conc. to give 396mg of crude orange oil. This was purified by chromatography on SiO₂ (25g cartridge, eluting with 0-6% MeOH/DCM over 330 mL) to give the product(136 mg, 0.256 mmol, 100%) as an orange oil.

LCMS (2 min Formic): Rt=1.02 min, [MH]⁺=532.

Intermediate 327: benzyl((2S,3S,4R)-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

4-Fluoroaniline (3 g, 27.0 mmol) and acetaldehyde (2.287 mL, 40.5 mmol)were taken up in DCM (120 mL) and allowed to stir at rt for 1 h. Thereaction was then cooled to 0° C. and was treated with (E)-benzylprop-1-en-1-ylcarbamate (fora preparation see Intermediate 1, 5.68 g,29.7 mmol) and2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.156 g, 0.270mmol). The reaction was allowed to stir at 0° C. for 3 h, then thesolution was decanted into a separating funnel. The mixture was washedwith saturated sodium bicarbonate solution (200 mL), giving a denseemulsion, from which the organic layer was separated after half an hourof waiting, and the aqueous extracted with DCM (2×50 mL). The organicphase was dried over sodium sulphate and evaporated in vacuo, giving acolourless solid. This was dissolved in hot EtOAc (30 mL), thencyclohexane (around 50 mL) was added, giving a suspension. This washeated to reflux, giving a clear, colourless solution, which was thenallowed to stand and cooled to room temperature, then cooled further inan ice bath and the resulting suspension filtered to give the desiredproduct as a colourless solid (3.85 g, 11.72 mmol, 43%). Analysis bychiral HPLC was undertaken using a 250×4.6 mm Chiralpak IC columneluting with 5% ethanol in heptane (containing 0.1% isopropylamine) at aflow rate of 1 mL/min. Peak 1/minor enantiomer (2.7% by UV) eluted at10.3 min, and Peak 2/major enantiomer (97.3% by UV) eluted at 11.4 min.This indicated the product had an ee of >94%. LCMS (2 min HpH): Rt=1.17min, [MH]⁺=329.

Intermediate 328: benzyl((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Benzyl((2S,3S,4R)-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(For a preparation see Intermediate 327, 3.8 g, 11.57 mmol) wasdissolved in DCM (50 mL) and pyridine (2.81 mL, 34.7 mmol) was added.The solution was cooled in an ice bath and acetyl chloride (0.987 mL,13.89 mmol) was added dropwise over 5 min, then the mixture stirred for1 hr at 0° C. The reaction mixture was washed with 1M HCl (50 mL), water(50 mL) and sodium bicarbonate solution (50 mL), dried and evaporated invacuo to give the desired product as a pink solid (4.1 g, 11.07 mmol,96%). LCMS (2 min HpH): Rt=1.08 min, [MH]⁺=371.

Intermediate 329:1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of benzyl((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(For a preparation see Intermediate 328, 4.02 g, 10.85 mmol) in EtOH (50mL) was added to 10 wt. % palladium on carbon (402 mg, 3.78 mmol) andthe mixture stirred under an atmosphere of hydrogen at r.t. for 16 hr.The reaction mixture was filtered through celite and the cake washedwith EtOH (80 mL). The filtrate was evaporated in vacuo and dried in avacuum oven to give the desired product as a yellow oil (2.36 g, 9.99mmol, 92%).

LCMS (2 min Formic): Rt=0.41 min, [MH]⁺=237 and [M-NH₂]⁺=220 observed.

Intermediate 330: benzyl((2S,3S,4R)-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The 4-fluoroaniline (7 g, 63.0 mmol) and cyclopropanecarbaldehyde (7.05mL, 94 mmol) were taken up in DCM (200 mL) and allowed to stir at rt for1 h. The reaction was then cooled to 0° C. and was treated with(E)-benzyl prop-1-en-1-ylcarbamate (for a preparation see Intermediate1, 13.25 g, 69.3 mmol) and2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.364 g, 0.630mmol). The reaction was allowed to stir at 0° C. for 20 h. The reactionwas washed with NaHCO_(3 (aq)), the aqueous phase was washed with EtOAcand the combined organics were dried using a hydrophobic frit andconcentrated to give a yellow/orange solid. This solid wasrecrystallised twice from EtOAc:cyclohexane to give the desired productas a white solid (6.123 g, 17.28 mmol, 27%). Analysis by chiral HPLC wasundertaken using a 250×4.6 mm Chiralcel OJ column eluting with 25%ethanol in heptane at a flow rate of 1 mL/min. Peak 1/minor enantiomer(5.5% by UV) eluted at 11.9 min, and Peak 2/major enantiomer (94.5% byUV) eluted at 14.8 min. This indicated the product had an ee of 89%.LCMS (2 min Formic): Rt=1.19 min, [MH]⁺=355.

Intermediate 331: benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The benzyl((2S,3S,4R)-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see intermediate 330, 6.12 g, 17.27 mmol) was takenup in DCM (200 mL) and treated with DIPEA (6.03 mL, 34.5 mmol) andacetyl chloride (2.456 mL, 34.5 mmol), the resulting yellow solution wasallowed to stir at rt for 16 hr. The reaction was washed withNaHCO_(3 (aq)) and NH₄Cl_((aq)) dried using a hydrophobic frit andconcentrated and dried to give a pale yellow solid. This solid wassuspended in Et₂O, sonicated and the resulting cream suspension wasremoved by filtration and dried to give the desired product (5.865 g,14.79 mmol, 86%) as a white solid.

LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=397.

Intermediate 332:1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 331, 5 g, 12.61 mmol) and 10% Pd/C(0.9 g, 8.46 mmol) in ethyl acetate (100 mL) was stirred under anatmosphere of hydrogen at room temp for 16 hr. The reaction mixture wasfiltered through celite, rinsed with ethyl acetate and concentrated invacuo to give the desired product (2.8 g, 10.67 mmol, 85% yield).

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=263 (weakly) and [(M−NH4)+]=246observed.

Intermediate 333:1-((2S,3R,4R)-6-fluoro-4-((2-methoxypyrimidin-4-yl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

In a test tube1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 329, 20 mg, 0.085 mmol),4-bromo-2-methoxypyrimidine (19.20 mg, 0.102 mmol), sodium tert-butoxide(16.27 mg, 0.169 mmol), Pd₂(dba)₃ (3.88 mg, 4.23 μmol) and DavePhos(3.33 mg, 8.46 μmol) were dissolved in 1,4-dioxane (1 mL). Using agreenhouse apparatus the solution was stirred and heated at 100° C.overnight. The reaction mixture was allowed to cool and was thenfiltered through celite washing through with extra 1,4-dioxane. Thefiltrate was concentrated in vacuo to leave the crude product.Purification was undertaken using MDAP (Formic). Evaporation of thedesired fractions gave the desired product as a white solid (10 mg,0.029 mmol, 34%). LCMS (2 min Formic): Rt=0.60 min, [MH]⁺=345.

Intermediate 334:1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((2-methoxypyrimidin-4-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 332, 75 mg, 0.286 mmol),4-bromo-2-methoxypyrimidine (64.8 mg, 0.343 mmol), DavePhos (11.25 mg,0.029 mmol), Pd₂(dba)₃ (13.09 mg, 0.014 mmol) and sodium tert-butoxide(27.5 mg, 0.286 mmol) was stirred under nitrogen for 8 hr. The reactionmixture was allowed to cool to room temp, filtered through Celite andrinsed with ethyl acetate. The solvent was evaporated in vacuo and afurther portion of 4-bromo-2-methoxypyrimidine (64.8 mg, 0.343 mmol),DavePhos (11.25 mg, 0.029 mmol), Pd₂(dba)₃ (13.09 mg, 0.014 mmol) andsodium tert-butoxide (27.5 mg, 0.286 mmol) were added. 1,4-Dioxane (2mL) was added and the solution was once again stirred under nitrogen at90° C. for 72 hr. The reaction mixture was allowed to cool to room temp,filtered through celite and rinsed with ethyl acetate. Once the solventhad been removed in vacuo, the sample was dissolved in 1:1 MeOH:DMSO 1mL and purified by MDAP (HpH) to give the desired product (26 mg, 0.070mmol, 25%).

LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=371.

Intermediate 335:1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((2-methoxypyridin-3-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 332, 75 mg, 0.286 mmol),3-bromo-2-methoxypyridine (0.041 mL, 0.343 mmol), DavePhos (11.25 mg,0.029 mmol), Pd₂(dba)₃ (13.09 mg, 0.014 mmol) and sodium tert-butoxide(27.5 mg, 0.286 mmol) was stirred under nitrogen at 90° C. for 8 hr. Thereaction mixture was allowed to cool to room temp, filtered throughcelite and rinsed with ethyl acetate. The solvent was evaporated invacuo and a further portion of 3-bromo-2-methoxypyridine (0.041 mL,0.343 mmol), DavePhos (11.25 mg, 0.029 mmol), Pd₂(dba)₃ (13.09 mg, 0.014mmol) and sodium tert-butoxide (27.5 mg, 0.286 mmol) was added.1,4-Dioxane (2 mL) was added and the solution was once again stirredunder nitrogen at 90° C. for 72 hr. The reaction mixture was allowed tocool to room temp, filtered through celite and rinsed with ethylacetate. Once the solvent had been removed in vacuo, the sample wasdissolved in DCM, loaded onto a 25 g silica cartridge and purified overa gradient of 0-100% ethyl acetate in cyclohexane over 12 CVs. Theappropriate fractions were combined and concentrated in vacuo to affordthe desired product (49 mg, 0.133 mmol, 46%). LCMS (2 min Formic):Rt=1.14 min, [MH]⁺=370.

Intermediate 336:1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((3-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 332, 75 mg, 0.286 mmol),2-bromo-3-methoxypyridine (64.5 mg, 0.343 mmol), DavePhos (11.25 mg,0.029 mmol), Pd₂(dba)₃ (13.09 mg, 0.014 mmol) and sodium tert-butoxide(27.5 mg, 0.286 mmol) in 1,4-dioxane (1 mL) was stirred under nitrogenat 90° C. for 8 hr. The reaction mixture was allowed to cool to rt,filtered through celite and rinsed with ethyl acetate. The solvent wasevaporated in vacuo and a further portion of 2-bromo-3-methoxypyridine(64.5 mg, 0.343 mmol), DavePhos (11.25 mg, 0.029 mmol), Pd₂(dba)₃ (13.09mg, 0.014 mmol) and sodium tert-butoxide (27.5 mg, 0.286 mmol)1,4-dioxane (1 mL) were added. The solution was once again stirred undernitrogen at 90° C. for 72 hr. The reaction mixture was allowed to coolto room temp, filtered through Celite and rinsed with ethyl acetate.Once the solvent had been removed in vacuo, the sample was dissolved inDCM, loaded onto a 25 g silica cartridge and purified over a gradient of0-100% ethyl acetate in cyclohexane over 12 CVs. The appropriatefractions were combined and concentrated in vacuo to give the desiredproduct (87 mg, 0.235 mmol, 82%). LCMS (2 min Formic): Rt=0.74 min,[MH]⁺=370.

Intermediate 337:6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

A solution of1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(fora preparation see Intermediate 332, 150 mg, 0.572 mmol),6-fluoronicotinonitrile (140 mg, 1.144 mmol) and triethylamine (0.159mL, 1.144 mmol) in N,N-dimethylformamide (DMF) (3 mL) was stirred in aμwave at 150° C. for 2.5 h. The reaction mixture was purified directly(3 injections of 1 ml DMF) by MDAP (Formic). The appropriate fractionswere combined and concentrated in vacuo to give the product (96 mg,0.263 mmol, 46%).

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=364.

Intermediate 338:6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinonitrile

In a flask were added1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 332, 150 mg, 0.572 mmol),6-bromopicolinonitrile (157 mg, 0.858 mmol), sodium tert-butoxide (110mg, 1.144 mmol) and Pd(QPhos)₂ (87 mg, 0.057 mmol) in toluene (4 mL).Reaction mixture was stirred under nitrogen at 50° C. for 3 h. A furtherportion of Pd(QPhos)₂ (43.7 mg, 0.029 mmol) was added and reactionmixture left stirring at 50° C. in the stirrer plate overnight. Reactionmixture was concentrated in vacuo to afford 561.9 mg of red gum crude.Resulting crude was purified by silica gel chromatography, 25 g column,0-3% 2M NH₃ in MeOH in DCM gradient over 15 column volumes. Relevantfractions were combined and volatiles were removed under reducedpressure to afford 177 mg of red gum. This compound was repurified bysilica gel chromatography, (25 g column, 15-75% EtOAc in cyclohexaneover 20 CVs). Relevant fractions were combined and volatiles wereremoved under reduced pressure to afford the desired product as a palered gum which was used directly in the next step without furtherpurification. 143 mg, 0.392 mmol, 69%)

LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=365.

Intermediate 339:2-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-6-methylnicotinonitrile

A mixture of1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 329, 150 mg, 0.635 mmol), sodiumtert-butoxide (122 mg, 1.270 mmol), Pd(QPhos)2 (24 mg, 0.016 mmol) and2-chloro-6-methylnicotinonitrile (145 mg, 0.952 mmol) in anhydroustoluene (2 mL) was evacuated and purged with nitrogen (×3) and stirredunder nitrogen at 50° C. for 17 h. The reaction mixture was filteredthrough a 2.5 g celite cartridge and the cartridge then washed withEtOAc (25 mL). The filtrate was evaporated in vacuo and the gumdissolved in DCM (1 mL). The solution was purified by silica gel columnchromatography (25 g column, 0-100% EtOAc in DCM over 10 CVs). Theappropriate fractions were combined and the solvent removed by rotaryevaporation to give the desired product as an off-white solid (20 mg,0.057 mmol, 9%).

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=353.

Intermediate 340: methyl4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate

In a 100 mL RB flask were added1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(For a preparation see Intermediate 332, 1006.2 mg, 3.84 mmol), methyl4-bromobenzoate (1262 mg, 5.87 mmol), cesium carbonate (2496 mg, 7.66mmol), and Pd(QPhos)₂ (584 mg, 0.382 mmol) in cyclopentylmethylether (10mL). The reaction mixture was degassed with nitrogen for 20 min andstirred at 80° C. for 3.5 h. A further portion of Pd(QPhos)₂ (293 mg,0.192 mmol) was added and mixture left stirring at same 80° C.overnight. Reaction mixture was partitioned between water and EtOAc.Aqueous phase was extracted with EtOAc (×3). Organic layers werecombined and washed with brine, dried over Na₂SO₄, filtered throughhydrophobic cartridge and volatiles removed under reduce pressure toafford 2.7 g of dark red gum. The crude product was purified by silicagel chromatography, (100 g column, 0-4% 2M NH₃ in MeOH in DCM gradientover 15 CVs). Relevant fractions were combined and volatiles wereremoved under reduce pressure to afford the desired product as a redpowder (1.82 g, 3.07 mmol, 80%).

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=397.

Intermediate 341:4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoicacid

Methyl4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate(for a preparation see Intermediate 341, 1822 mg, 4.60 mmol) and lithiumhydroxide monohydrate (964 mg, 22.98 mmol) were dissolved in THE (10 mL)and water (10 mL). The reaction was stirred at rt for 15 h. A furtherportion of lithium hydroxide monohydrate (964 mg, 22.98 mmol) was addedand reaction mixture left stirring at rt for 3 h. Sodium hydroxide (919mg, 22.98 mmol) was added and reaction mixture was stirred at rtovernight. The reaction mixture was heated at 50° C. for 30 min. Lithiumhydroxide monohydrate (964 mg, 22.98 mmol) and sodium hydroxide (919 mg,22.98 mmol) were added. The reaction mixture was left stirring at 60° C.for 4.5 days. The reaction mixture was cooled down to rt. Mixture wasdiluted with water and washed with EtOAc. The aqueous layer was thenacidified with 1M HCl (to pH=4) and filtered to obtain the desiredproduct as a brown solid (1.3632 g, 3.588 mmol, 78%).

LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=383.

Intermediate 342: tert-butyl4-((6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2-yl)methyl)piperazine-1-carboxylate

In a 50 mL RB flask were added1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 332, 48.9 mg, 0.186 mmol),tert-butyl 4-((6-bromopyridin-2-yl)methyl)piperazine-1-carboxylate (fora preparation see Intermediate 233, 64.4 mg, 0.181 mmol), Pd₂(dba)₃(21.7 mg, 0.024 mmol), sodium tert-butoxide (38.2 mg, 0.397 mmol) andQPhos (16.7 mg, 0.023 mmol) in toluene (3 mL). Reaction mixture wasstirred at 50° C. under nitrogen overnight. A further portion ofPd₂(dba)₃ (17.07 mg, 0.019 mmol), sodium tert-butoxide (8.96 mg, 0.093mmol) and QPhos (13.29 mg, 0.019 mmol) were added and reaction mixturewas left stirring under same conditions for 2 h. Reaction mixture wasallowed to cool down at rt and left to stand overnight. The reactionmixture was filtered through celite cartridge and partitioned betweenwater and EtOAc. Aqueous phase was extracted with EtOAc (×3). Organiclayers were combined and washed with brine, dried over Na₂SO₄, filteredthrough hydrophobic cartridge and volatiles removed under reducepressure to afford 155.1 mg of orange gum. This resulting crude productwas purified by silica gel chromatography (25 g column, 1-5% 2M NH₃ inMeOH in DCM in gradient over 20 CVs). Relevant fractions were combinedand volatiles were removed under reduce pressure to afford the desiredproduct as a yellow gum (87.4 mg, 0.157 mmol, 87%). LCMS (2 min Formic):Rt=0.92 min, [MH]⁺=538.

Intermediate 343: (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate

To a microwave vial was added (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 179, 50 mg, 0.113 mmol) in1,4-dioxane (2.5 mL). To this was added 2-bromo-4-methylpyrimidine (39.1mg, 0.226 mmol), Pd₂(dba)₃ (20.69 mg, 0.023 mmol), sodium tert-butoxide(32.6 mg, 0.339 mmol) and DavePhos (26.7 mg, 0.068 mmol). The vessel wassealed and heated in a microwave reactor at 120° C. for 40 min. Afurther 2 eq 2-bromo-4-methylpyrimidine (39.1 mg, 0.226 mmol) was added,the vessel resealed and the reaction heated to 120° C. for 30 minutes.The reaction mixture was filtered over a 2.5 g celite cartridge, washedthrough with ethyl acetate and concentrated in vacuo. The residue wasdissolved in 1:1 MeOH:DMSO 1 mL and purified by MDAP (Formic). Thesolvent was evaporated in vacuo to give the required product (18 mg).

LCMS (2 min Formic): Rt=1.17 min, [MH]⁺=535.

Intermediate 344:1-((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A sample of benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 219, 2.5 g, 5.47 mmol) and potassiumhydroxide (3.07 g, 54.7 mmol) were added to a flask, and to this wasadded water (50 mL) and ethanol (50 mL), forming a suspension. Thereaction vessel was heated to 80° C. for 16 h. After this time a yellowsolution had formed. A further portion of KOH (307 mg, 5.47 mmol) wasadded and the reaction heated to 80° C. for a further 4 h and then to90° C. with stirring for a further 1.5 h. The reaction was allowed tocool to rt and water (150 mL) and DCM (150 mL) were added. The layerswere separated and the aqueous layer further extracted with DCM (2×50mL). The combined organics were dried (Na₂SO₄) and concentrated in vacuoto afford the crude product as a yellow oil. The crude product was takenup in DCM and added to a SNAP silica cartridge (100 g). This waspurified by flash chromatography, eluting with 0%->20% (20% (2M NH₃ inMeOH)/DCM)/DCM. The appropriate fractions were collected andconcentrated in vacuo to afford the desired product as a whitecrystalline solid (1.27 g, 3.93 mmol, 72%).

LCMS (2 min Formic): Rt=0.57 min, [M-NH₂]⁻=323, 325.

Intermediate 345:1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

The2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(390 mg, 1.856 mmol),1-((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 344,400 mg, 1.238mmol) and caesium carbonate (1210 mg, 3.71 mmol) were suspended in1,4-dioxane (15 mL):water (1.5 mL) and treated with Pd(PPh₃)₄ (143 mg,0.124 mmol). The reaction was allowed to stir at 80° C. for 16 h. Thereaction was partitioned between water and EtOAc, the aqueous layer wasextracted with EtOAc and the combined organics were washed with brine,dried (Na₂SO₄) and concentrated in vacuo to a dark oil. This oil waspurified using a by flash chromatography using a SNAP (100 g) Si column,eluting with 0-25% (20% 2M NH₃ in MeOH in DCM)/DCM. The appropriatefractions were summed and concentrated to give impure product. Thereforethe column was re-eluted with 25%->50% (20% 2M NH₃ in MeOH in DCM)/DCM.The appropriate fraction was collected and concentrated in vacuo toafford the desired product as a yellow oil (213 mg, 0.653 mmol, 53%).

LCMS (2 min Formic): Rt=0.60 min, [M-NH₂]⁺=310.

Intermediate 346: benzyl((2S,3R,4R)-1-acetyl-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a reaction vessel, 2-((tert-butyldimethylsilyl)oxy)ethanol (0.433 mL,2.186 mmol), benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 219, 500 mg, 1.093 mmol),5-(di(adamantan-1-yl)phosphino)-1′,3′,5′-triphenyl-1′H-1,4′-bipyrazole(145 mg, 0.219 mmol), Pd(OAc)₂ (49.1 mg, 0.219 mmol) and Cs₂CO₃ (712 mg,2.186 mmol) were added in toluene (10 mL) and the reaction left to stirfor 2 h at 90° C. The reaction mixture was allowed to cool to rt andthen filtered through celite. The filtrate was washed with water (2×35mL) and the layers separated. The organic layer was dried through ahydrophobic frit and concentrated in vacuo to give 774 mg of crudeproduct as a pale yellow solid. This was purified by chromatography onSiO₂ (50 g) eluting with 0-30% ethyl acetate/cyclohexane. The fractionscontaining product were combined and concentrated in vacuo to give 335mg of impure product as an off-white solid. The sample was dissolved in1:1 MeOH:DMSO 6 mL and purified by 2×MDAP (HpH). The solvent wasevaporated in vacuo to give 190 mg of the product (190 mg, 0.344 mmol,31%) as an off-white solid. LCMS (2 min Formic): Rt=1.48 min, [MH]⁺=553.

Intermediate 347:1-((2S,3R,4R)-4-amino-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Benzyl((2S,3R,4R)-1-acetyl-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 346, 190 mg, 0.344 mmol) was takenup in ethanol (10 mL). The solution was hydrogenated using the H-cube(settings: rt, 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart as thecatalyst. The solution was left to cycle through the H-cube for afurther 1 h. The reaction mixture was concentrated in vacuo to give thedesired product (130 mg, 0.311 mmol, 90%) as a white solid.

LCMS (2 min Formic): Rt=1.01 min, [M-NH₂]⁺=402.

Intermediate 348:1-((2S,3R,4R)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel1-((2S,3R,4R)-4-amino-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 347, 125 mg, 0.299 mmol),2-bromo-4-methylpyrimidine (77 mg, 0.448 mmol) and sodium tert-butoxide(143 mg, 1.493 mmol) were added in 1,4-dioxane (10 mL). This solutionwas treated with Pd₂(dba)₃ (41.0 mg, 0.045 mmol) and DavePhos (24 mg,0.061 mmol) and left to stir at 100° C. for 3 h. The reaction mixturewas filtered through celite and washed with water (2×25 mL). The layerswere separated and the organic phase dried through a hydrophobic frit.The organic phase was then concentrated in vacuo to give 178 mg of crudeproduct as an orange gum. This was purified by chromatography on SiO₂ 10g column, eluting with 0-100% ethyl acetate/cyclohexane. The fractionscontaining product were combined and concentrated in vacuo to give 43 mgof the product as an orange solid.

LCMS (2 min Formic): Rt=1.37 min, [MH]⁺=511.

Intermediate 349: benzyl((2R,3R,4R)-1-acetyl-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

The1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(551 mg, 2.186 mmol), benzyl((2R,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 219, 500 mg, 1.093 mmol),PdCl₂(dppf) (64.0 mg, 0.087 mmol) and potassium carbonate (332 mg, 2.405mmol) were taken up in water (10 mL):1,4-dioxane (30 mL) and allowed tostir at 85° C. for 2 h. The reaction was treated with furtherPdCl₂(dppf) (80 mg, 0.109 mmol) and allowed to stir at 85° C. undernitrogen for 1 h. The reaction was allowed to cool to rt and wasconcentrated to remove the 1,4-dioxane and was partitioned between waterand EtOAc, the aqueous layer was extracted with further EtOAc, thecombined organics were washed with brine, dried using a hydrophobic fritand concentrated to an orange gum. This gum was purified using a 25 g Sicolumn, elute 0-100% EtOAc:cyclohexane. The appropriate fractions weresummed and concentrated to give the product (433 mg, 0.862 mmol, 79%) asan orange solid. LCMS (2 min Formic): Rt=1.03 min, [M-NH₂]⁺=503.

Intermediate 350:1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

The benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 349, 433 mg, 0.862 mmol) was takenup in ethanol (10 mL). The reaction was hydrogenated using the H-cube(settings: 25° C., 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart 30 asthe catalyst. The solution was allowed to cycle through the machine for4 h. The reaction was concentrated to give the product (408 mg) as ayellow oil which contained some solvent and minor impurities but wasused as was in the subsequent step. LCMS (2 min Formic): Rt=0.58 min,[M-NH₂]⁺=369.

Intermediate 351:2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol

A solution of 1,3-dioxolan-2-one (1.902 mL, 28.5 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.0239 g,25.9 mmol) and sodium hydroxide (0.0998 g, 2.495 mmol) inN,N-dimethylformamide (DMF) (20 mL) was heated to 140° C. overnight. Themixture was cooled down to rt and then activated charcoal (200 mg) wasadded and this was stirred for 4 h before filtering through celitecartridge (10 g). The mixture was washed with EtOAc (50 mL) and EtOH (50mL and the combined filtrate was concentrated in vacuo to afford 7.53 gof brown oil. This was used crude in further reactions. LCMS: Notrecorded.

Intermediate 352:1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

1-((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 344, 860 mg, 2.66 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol(for a preparation see Intermediate 351, 950 mg, 3.99 mmol), potassiumcarbonate (1103 mg, 7.98 mmol) and Pd(PPh₃)₂Cl₂ (374 mg, 0.532 mmol)were combined in a mixture of 1,4-dioxane (12 mL) and water (4 mL) andheated in the microwave reactor at 120° C. for 1 h. The reaction mixturewas diluted with ethyl acetate and water and combined with the reactionmixture from the same reaction carried out on 200 mg of starting THQ.The organic layer was separated, dried and evaporated in vacuo to give˜2.3 g of crude orange oil. This was dissolved in the minimum amount ofMeOH (˜5 mL) and loaded onto a 50 g SCX cartridge (pre-conditioned withMeOH). This was then eluted with MeOH (200 mL) followed by 2M NH₃ inMeOH (300 mL). Ammonia fractions containing desired product by TLC werecombined and concentrated in vacuo to give 1.29 g of yellow oil. Thiswas further purified by chromatography on SiO₂ (100 g cartridge, elutingwith 0-20% methanol/DCM over 1300 mL) to give the product (645 mg, 1.820mmol, 68%) as a pale yellow foamy solid. LCMS (2 min Formic): Rt=0.51min, [M-NH₂]⁺=338.

Intermediate 353:1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol(for a preparation see Intermediate 351, 1.057 g, 4.44 mmol) inN,N-dimethylformamide (DMF) (5 mL) was added imidazole (3 g, 44.1 mmol)and TBDMSCl (3.35 g, 22.20 mmol) and reaction mixture stirred at rt.After 2 h a catalytic amount of DMAP was added and reaction mixture wascontinued to stir at rt overnight. The reaction mixture diluted withwater and diethyl ether. The organic layer was separated and the aqueouslayer extracted with further portions of diethyl ether (2×50 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated to give2.82 g of crude pale yellow oil. This was further purified bychromatography on SiO₂ (100 g cartridge, eluting with 0-100% ethylacetate/cyclohexane over 1320 mL, collecting all fracations andvisualising with KMnO4) to give the product (712 mg, 2.021 mmol, 46%) asa colourless oil LCMS: (2 min Formic): Rt=1.40 min, [MH]⁺=353.

Intermediate 354:1-((2S,3R,4R)-4-amino-6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

1-((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 344, 200 mg, 0.619 mmol),1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(for a preparation see Intermediate 353, 436 mg, 1.238 mmol), potassiumcarbonate (257 mg, 1.856 mmol) and Pd(PPh₃)₂Cl₂ (87 mg, 0.124 mmol) werecombined in a mixture of 1,4-dioxane (3 mL) and water (1.0 mL) andheated in the microwave reactor at 120° C. for 1 h. The reaction mixturewas diluted with EtOAc (50 mL) and water (50 mL) and the organic layerwas separated, dried and evaporated in vacuo to give the crude.Purification was undertaken by flash column chromatography. The crudematerial was loaded onto a 25 g silica column and eluted using agraduating solvent system of 0-10% 2M methanolic ammonia indichloromethane. Combination and evaporation of the desired fractionsgave the product as a yellow oil (190 mg). LCMS (2 min Formic): Rt=0.89min, [M-NH₂]⁺=452.

Intermediate 355:1-((2S,3R,4R)-6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

1-((2S,3R,4R)-4-Amino-6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 354, 190 mg, 0.405 mmol),2-bromopyridine (0.058 mL, 0.608 mmol), sodium tert-butoxide (78 mg,0.811 mmol), Pd₂(dba)₃ (18.56 mg, 0.020 mmol) and Q-Phos (28.9 mg, 0.041mmol) were combined in anhydrous toluene (2 mL). The reaction was heatedat 50° C. overnight. The reaction was incomplete so further2-bromopyridine (0.058 mL, 0.608 mmol), sodium tert-butoxide (78 mg,0.811 mmol), Pd₂(dba)₃ (18.56 mg, 0.020 mmol) and Q-Phos (28.9 mg, 0.041mmol) were added and heating was continued for 5 h. The reaction mixturewas partitioned between EtOAc (50 mL) and water (50 mL). The organiclayer was separated and passed through a hydrophobic frit. The filtratewas concentrated in vacuo to leave the crude. Purification wasundertaken by flash column chromatography. The crude material was loadedonto a 25 g silica column and eluted using a graduating solvent systemof 0-75% EtOAc in cyclohexane. Combination and evaporation of thedesired fractions gave the product as a red oil (70 mg). LCMS (2 minFormic): Rt=0.99 min, [MH]⁺=546.

Intermediate 356:1-((2S,3R,4R)-4-amino-6-bromo-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A sample of benzyl((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 209, 3.0268 g, 7.02 mmol) wasdissolved in ethanol (64 mL), and to this was added water (64 mL),forming a suspension. To the suspension was added potassium hydroxide(3.985 g, 71.0 mmol). The mixture was stirred at 80° C. for 4 h. Thereaction temperature was raised to 90° C. and allowed to stir overnight.The reaction mixture was allowed to cool, diluted with water and washedwith dichloromethane (75 mL). The layers were separated, and the aqueouslayer was washed two further times with dichloromethane (2×75 mL). Theorganic layers were passed over a hydrophobic frit, combined andconcentrated in vacuo to afford a yellow oil. This oil was dissolved inmethanol and loaded onto a 50 g SCX-2 SPE cartridge which had beenpre-equilibrated with methanol. The column was flushed through with 4CVs of methanol, and then 4 CVs of 2M ammonia in methanol. Theappropriate fractions were combined and concentrated in vacuo to afforda colourless oil (1.17 g, 3.94 mmol, 56%).

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=297, 299.

Intermediate 357: tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A sample of1-((2S,3R,4R)-4-amino-6-bromo-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(1.17 g, 3.94 mmol) was dissolved in a mixture of 1,4-dioxane (40 mL)and water (4.00 mL) under nitrogen. To this stirring solution was addedtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 356, 1.357 g, 4.39 mmol), caesiumcarbonate (1.283 g, 3.94 mmol) and palladium tetrakis (0.455 g, 0.394mmol). The mixture was stirred at 80° C. under nitrogen for ˜3.5 hours.A further sample of caesium carbonate (2.57 g, 7.87 mmol) was added, andthe mixture left to cool to rt over a 4 day period. A further sample ofpalladium tetrakis (0.455 g, 0.394 mmol) was added, and the reactionmixture was again stirred at 80° C. overnight. The reaction mixture wasallowed to cool to rt, and concentrated in vacuo. The residue wasseparated between ethyl acetate and water, and the aqueous layer waswashed twice more with ethyl acetate. The organic layers were combined,passed through a hydrophobic frit and concentrated in vacuo to form anorange oil. The oil was dissolved in dichloromethane and loaded onto a100 g silica flash column, and eluted by silica gel flash chromatographyusing 0%-10% methanol in dichloromethane. The appropriate fractions werecollected and concentrated in vacuo to afford the product (502.7 mg,1.258 mmol, 32%).

LCMS (2 min Formic): Rt=0.81 min, [MH]⁺=383.

Intermediate 358: tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a 10 mL-20 mL microwave vial was added 2-chloro-4-methylpyrimidine(421 mg, 3.27 mmol), potassium fluoride (285 mg, 4.91 mmol) and18-crown-6 (432 mg, 1.636 mmol), followed by a solution of tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (for a preparation see Intermediate 357, 435.7 mg,1.091 mmol) in dimethyl sulfoxide (DMSO) (12 mL). The reaction vesselwas sealed and heated to 160° C. for ˜40 minutes. Some DIPEA (0.952 mL,5.45 mmol) was added, and the vessel was resealed and heated at 160° C.for 4 h. The reaction mixture was diluted with diethyl ether, washedwith water and the layers separated. The aqueous layer was extractedtwice more with diethyl ether. The organic layers were combined andback-washed a further 2 times with water. The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo. The residue wastaken up in dichloromethane and loaded onto a 100 g silica flash column,and purified by silica gel flash chromatography, eluting in 55%-75%ethyl acetate in cyclohexane. The appropriate fractions were collectedand concentrated in vacuo to afford a yellow oil (27%).

LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=492.

Intermediate 359:1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A sample of tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 358, 60.4 mg, 0.123 mmol) was placedin a flask under nitrogen and dissolved in dichloromethane (DCM) (2 mL).The solution was stirred, and to this was added trifluoroacetic acid(0.5 mL, 6.49 mmol). The mixture was allowed to stir at rt for 1 h. Thereaction mixture was diluted with dichloromethane and concentrated invacuo. The residue was dissolved in methanol and loaded onto a 2 g SCX-2SPE column, which had been pre-equilibrated with methanol. The columnwas flushed with 4 CVs of methanol, and then the product eluted using 3CVs of 2M NH₃ in methanol. The appropriate fractions were collected andconcentrated in vacuo to afford a yellow glass (44.5 mg, 0.097 mmol,79%). LCMS (2 min Formic): Rt=0.57 min, [MH]⁺=392.

Intermediate 360: rac-4-((tetrahydrofuran-3-yl)oxy)aniline

The N-oxo-N-(4-((tetrahydrofuran-3-yl)oxy)phenyl)hydroxylammonium (1.063g, 5.06 mmol) was taken up in acetic acid (15 mL) and allowed to stir at0° C., zinc (3.31 g, 50.6 mmol) was added portion-wise and the reactionallowed to warm to rt over 2 h. The reaction was concentrated and elutedthrough a NH₂ SPE (5 g) using MeOH, the MeOH was concentrated in vacuoto give 1.163 g of desired product (1.163 g, 4.69 mmol, 93%) as a brownsolid.

LCMS (2 min Formic): Rt=0.35 min, [MH]⁺=180.

Intermediate 361: benzyl((2S,3S,4R)-2,3-dimethyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of acetaldehyde (0.524 mL, 11.16 mmol) in anhydrousdichloromethane (DCM) (20 mL), was addedrac-4-((tetrahydrofuran-3-yl)oxy)aniline (for a preparation seeIntermediate 360, 400 mg, 2.232 mmol) and the reaction stirred at rt for1 h. The reaction was cooled to 0° C. and(S)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see for a preparation see JACS, 2011, 133,14804, 129 mg, 0.223 mmol) was added and then (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 750 mg,3.92 mmol) (500 mg added here). The reaction was then left to stir for 3h under nitrogen and allowed to warm to rt. Acetaldehyde (0.252 mL, 4.46mmol) and (E)-benzyl prop-1-en-1-ylcarbamate (750 mg, 3.92 mmol) (250mg) were added and the reaction left to stir at rt for 72 h. Thesolution was diluted with DCM (5 mL) and washed with aq. NaHCO₃ solution(30 mL). The layers were separated and the aqueous phase extracted withDCM (3×25 mL). The organics were combined, dried through a hydrophobicfrit, and concentrated in vacuo to give 451 mg the desired product (451mg, 1.138 mmol, 51%) as a yellow/brown solid. Analysis by chiral HPLCwas undertaken using a 250×4.6 mm Chiralpak ID column eluting with 20%isopropanol in heptane at a flow rate of 1 mL/min. Peak(s) 1/majorisomers (96% by UV) eluted at 26.5 & 39.8 min, and Peak(s) 2/minorisomers (4% by UV) eluted at 67.8 &73.4 min. This indicated the producthad an ee of 92% (about positions 2, 3 & 4). LCMS (2 min Formic):Rt=0.87 min, [M-NH₂]⁺=397.

Intermediate 362: benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a reaction mixture benzyl((2S,3S,4R)-2,3-dimethyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 361, 450 mg, 1.135 mmol) and DIPEA(0.595 mL, 3.40 mmol) were added in dichloromethane (DCM) (20 mL).Acetyl chloride (0.161 mL, 2.270 mmol) was added and the reaction leftto stir for 2 h at rt under nitrogen. The reaction mixture wasconcentrated in vacuo to give 1.003 g if crude product as a brown solid.This was purified by chromatography on SiO₂ (50 g), eluting with 0-100%ethyl acetate/cyclohexane. The fractions containing product werecombined and concentrated in vacuo to give 439 mg of the desired product(439 mg, 1.001 mmol, 88%) as a pale yellow gum.

LCMS (2 min Formic): Rt=0.98 min, [MH⁺]=439.

Intermediate 363:1-((2S,3R,4R)-4-amino-2,3-dimethyl-rac-6-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Benzyl((2S,3R,4R)-1-acetyl-2,3-dimethyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 362, 439 mg, 1.001 mmol) was takenup in ethanol (10 mL). The solution was hydrogenated using the H-cube(settings: rt, 1 bar, 1 mL/min flow rate) and 10% Pd/C CatCart as thecatalyst. The reaction mixture was concentrated in vacuo to give 300 mgof the desired product (300 mg, 0.986 mmol, 98%) as a yellow oil. LCMS(2 min Formic): Rt=0.48 min, [M-NH₂]⁺=288.

Intermediate 364: benzyl((2S,3S,4R)-2-cyclopropyl-3-methyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a solution of cyclopropanecarbaldehyde (0.334 mL, 4.46 mmol) inanhydrous dichloromethane (DCM) (30 mL), was added4-((tetrahydrofuran-3-yl)oxy)aniline (for a preparation see Intermediate360, 400 mg, 2.232 mmol) and the reaction stirred at rt for 1 h. Thereaction was cooled to 0° C. and(S)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 12.89 mg, 0.022mmol) was added and then (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 469 mg, 2.455 mmol). The reaction wasthen left to stir for 16 h under nitrogen and allowed to warm to rt. Thesolution was washed with sat. NaHCO₃ solution (2×20 mL) and the layersseparated. The organic phase was dried through a hydrophobic frit andconcentrated in vacuo to give 1.280 g of crude product as a brown gum.This was purified by chromatography on SiO₂ (50 g) eluting with 0-40%ethyl acetate/cyclohexane. The fractions containing product werecombined and concentrated in vacuo to give 665 mg of the desired product(665 mg, 1.574 mmol, 71%) as a white solid. Analysis by chiral HPLC wasundertaken using a 250×4.6 mm Chiralpak IC column eluting with 10%ethanol in heptane at a flow rate of 1 mL/min. Peak(s) 1/minor isomers(5% by UV) eluted at 18.7 & 20.2 min, and Peak(s) 2/major isomers (95%by UV) eluted at 46.8 & 58.1 min. This indicated the product had an eeof 90% (about positions 2, 3 & 4).

LCMS (2 min Formic): Rt=1.02 min, [MH⁺]=423.

Intermediate 365: benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a reaction mixture benzyl((2S,3S,4R)-2-cyclopropyl-3-methyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 364, 655 mg, 1.550 mmol) and DIPEA(0.812 mL, 4.65 mmol) were added in dichloromethane (DCM) (20 mL).Acetyl chloride (0.198 mL, 2.79 mmol) was added and the reaction left tostir for 45 mins at rt under nitrogen.

Acetyl chloride (0.05 mL, 0.703 mmol) was added and the reaction left tostir for 1 h under nitrogen at rt. The reaction solution wasconcentrated in vacuo to give 1.421 g of crude product as anorange/brown gum. This was purified by chromatography on SiO₂ (50 g)eluting with 0-75% ethyl acetate/cyclohexane. The fractions containingproduct were combined and concentrated in vacuo to give 674 mg of thedesired product (674 mg, 1.451 mmol, 94%) as a yellow gum.

LCMS (2 min Formic): Rt=1.05 min, [MH⁺]=465.

Intermediate 366:1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-rac-6-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-rac-6-((tetrahydrofuran-3-yl)oxy)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation se Intermediate 365, 664 mg, 1.429 mmol) was taken upin tetrahydrofuran (THF) (10 mL), TBAF 1M in THE (2.86 mL, 2.86 mmol)was added and the solution was stirred under reflux for 16 h. FurtherTBAF 1M in THF (1.429 mL, 1.429 mmol) was added and the reaction left tostir under N₂ and reflux for 1 h. Further TBAF 1M in THF (1.429 mL,1.429 mmol) was added and the reaction was left to stir under N₂ andreflux for 45 min. Further TBAF 1M in THF (2.86 mL, 2.86 mmol) was addedand the reaction was left to stir under N₂ and reflux for 45 min.Further TBAF 1M in THF (1.429 mL, 1.429 mmol) was added and the reactionwas left to stir for 40 min under N₂ and reflux. The solution waspartitioned between DCM and aq. NaHCO₃. The organic layer was separatedand the aqueous layer extracted with DCM (2×20 mL). The combined organicfractions were dried through a hydrophobic frit and concentrated invacuo to give a brown oil. The sample was loaded in methanol andpurified by SPE on sulphonic acid (SCX) 20 g using sequential solventsmethanol, 2M ammonia/methanol. The appropriate fractions were combinedconcentrated in vacuo to give 1.486 g of crude product as a brown oil.This was purified by chromatography on SiO₂ (100 g, eluting with 0-7% 2Mammonia in methanol/DCM). The fractions containing product were combinedand concentrated in vacuo to the product (277 mg, 0.838 mmol, 59%) as acolourless gum. LCMS (2 min Formic): Rt=0.56 min, [M-NH₂]⁺=314.

Intermediate 367: tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

A solution of 2-fluoropyrimidine (110 mg, 1.118 mmol), tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 213,150 mg, 0.373 mmol) and DIPEA(0.260 mL, 1.491 mmol) in dimethyl sulfoxide (DMSO) (2.6 mL) was addedto a microwave vial and the vial sealed and heated to 160° C. for 4 h.The reaction mixture was filtered, washed with a small amount of 1:1DMSO/MeOH directly into a vial and was purified by MDAP (HpH). Theappropriate fractions were collected and concentrated in vacuo to affordthe desired product as a beige oil (119 mg, 0.248 mmol, 66%) LCMS (2 minFormic): Rt=1.00 min, [MH]⁺=481.

Intermediate 368: tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-(methoxycarbonyl)phenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

To a 25 mL flask were added tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 213, 300 mg, 0.745 mmol), methyl4-bromobenzoate (226 mg, 1.051 mmol), cesium carbonate (456 mg, 1.400mmol), and Pd(QPhos)₂ (107 mg, 0.070 mmol) in CPME (1.8 mL). Thereaction mixture was degassed with nitrogen for 15 min and stirred at80° C. for 16 h. The reaction mixture was partitioned between EtOAc (20mL) and water (20 mL). The layers were separated and the aqueous layerwas further extracted with EtOAc (2×20 mL). The combined organics weredried (MgSO₄) and concentrated in vacuo to afford the crude product as ared oil. This was taken up in DCM and added to a silica cartridge (50g). This was eluted by flash chromatography, eluting with a gradient of0-60% EtOAc/cyclohexane. The appropriate fractions were collected andconcentrated in vacuo to afford the desired product as a red oil (308mg, 0.574 mmol, 77%).

LCMS (2 min Formic): Rt=1.18 min, [MH]⁺=537.

Intermediate 369:4-(((2S,3R,4R)-1-acetyl-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoicacid

tert-Butyl4-((2S,3R,4R)-1-acetyl-4-((4-(methoxycarbonyl)phenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 368, 300 mg, 0.559 mmol) and lithiumhydroxide (66.9 mg, 2.80 mmol) were dissolved in tetrahydrofuran (THF)(2.5 mL) and water (2.5 mL). The reaction was stirred at rt for 2 h andthen allowed to stand for ˜16 h at rt. Lithium hydroxide (69.6 mg, 2.91mmol) was added and the reaction was stirred vigorously at rt for 4 h.Sodium hydroxide (179 mg, 4.47 mmol) was added and the reaction left tostir at 55° C. for 4.5 h. The solution was allowed to cool to rt and thesolvent was evaporated in vacuo. The resulting solid was taken up inwater (40 mL) and acidified to a pH 3 at which point a white/purplesolid crashed out. This was filtered off and dried in vacuo to give 164mg of the crude product as a brown solid. The filtrate was extractedwith DCM (2×15 mL) and the layers separated. The organic phase was driedthrough a hydrophobic frit and concentrated in vacuo to give 221 mg ofthe crude product as a yellow solid. The two crude batches were combinedand purified by chromatography on SiO₂ (25 g, eluting with 0-100% ethylacetate/cyclohexane). The fractions containing product were combined andconcentrated in vacuo to give 164 mg of product as a white solid. Thecolumn was eluted again with 20% methanol/DCM, the fractions containingproduct were combined and concentrated in vacuo to give 75 mg of productas an off-white solid.

LCMS (2 min Formic): Rt=1.02 min, [MH]⁺=523.

Intermediate 370: tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-carbamoylphenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

To a solution of4-(((2S,3R,4R)-1-acetyl-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoicacid (for a preparation see Intermediate 369, 50 mg, 0.096 mmol) andHATU (43.7 mg, 0.115 mmol) in N,N-dimethylformamide (DMF) (0.8 mL),DIPEA (0.067 mL, 0.383 mmol) was added and the solution left to stir for1 minute then ammonium chloride (6.14 mg, 0.115 mmol) was added and thereaction left to stir at rt for 30 minutes. The solution was diluted to1 mL with methanol and purified by MDAP (Formic). The solvent wasevaporated in vacuo to give 52 mg of the desired product as a whitesolid.

LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=522.

Intermediate 371:1-((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 344, 300 mg, 0.928 mmol),2-fluoropyrimidine (182 mg, 1.856 mmol) and DIPEA (0.324 mL, 1.856 mmol)in N-methyl-2-pyrrolidone (NMP) (4.5 mL) was stirred in the microwave ina closed vessel at 200° C. for 1 h. The reaction mixture was dilutedwith ethyl acetate (10 mL) and washed with water (3×7 mL). The organiclayer was concentrated in vacuo. The crude was dissolved in DCM, loadedonto a 50 g silica cartridge and purified over a gradient of 0-100%ethyl acetate in cyclohexane over 12 CVs. The appropriate fractions werecombined and concentrated in vacuo to give the product (220 mg, 0.548mmol, 59%).

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=401, 403.

Intermediate 372: benzyl((2S,3S,4R)-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A solution of 4-bromoaniline (5 g, 29.1 mmol) and propionaldehyde (3.15mL, 43.6 mmol) in anhydrous dichloromethane (DCM) (150 mL) was stirredunder nitrogen at rt for 1 h and then cooled to 0° C. (ice bath).(11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 0.336 g, 0.581mmol) was added followed by (E)-benzyl prop-1-en-1-ylcarbamate (for apreparation see Intermediate 1, 5.93 g, 31.0 mmol) in anhydrous DCM (5mL). The reaction mixture was stirred at 0° C. (ice bath) and allowed toreach rt overnight (17 h). The reaction mixture was combined with themixture from another reaction (starting with 1.6 g aniline) then washedwith sat. aq. NaHCO₃ (140 mL) and the aqueous layer was extracted withDCM (100 mL). The combined organics were dried through a hydrophobicfrit and the solvent removed by rotary evaporation. The crude was loadedin DCM (10 mL) and purified by silica gel chromatography, (340 g) 0-10%EtOAc in cyclohexane gradient over 20 CV. The appropriate fractions werecombined and the solvent removed by rotary evaporation. The resultingwhite solid (12.6 g) was recrystallised in an EtOAc-cyclohexane (1-3)mixture and the recrystallised material was isolated by vacuumfiltration to give (after 2 hours in vacuum oven) the product (10.8 g,26.8 mmol, 92%) as a fine white crystals. Analysis by chiral HPLC wasundertaken using a 250×4.6 mm Chiralcel OJ column eluting with 25%ethanol in heptane at a flow rate of 1 mL/min. Peak 1/minor enantiomers(<0.5% by UV) eluted at 9.6 min, and Peak 2/major enantiomers (>99.5% byUV) eluted at 13.2 min. This indicated the product had an ee of >99%.LCMS (2 min Formic): Rt=1.28 min, [MH]⁺=403, 405.

Intermediate 373: benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a stirred solution of benzyl((2S,3S,4R)-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 372, 10.5 g, 26.0 mmol) and pyridine(6.0 ml, 74.2 mmol) in anhydrous dichloromethane (DCM) (252 mL) at 0° C.(ice bath) was added acetyl chloride (2.2 mL, 30.9 mmol) in anhydrousDCM (18 ml) drop-wise and the resulting mixture was stirred for 1 h,then allowed to reach rt. The reaction mixture was transferred to aseparating funnel and washed with 1M HCl (250 mL), water (250 mL) andsaturated sodium bicarbonate solution (250 mL), dried (phase separator)and evaporated in vacuo to give the product (11 g, 24.70 mmol, 95%) aslight white powder. LCMS (2 min Formic): Rt=1.17 min, [MH]⁺=445, 447.

Intermediate 374:1-((2S,3R,4R)-4-amino-6-bromo-2-ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A sample of benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 373, 2.57 g, 5.77 mmol) andpotassium hydroxide (3.22 g, 57.4 mmol) were added to a flask, and tothis was added water (40 mL) and ethanol (40 mL), forming a suspension.The reaction vessel was heated to 80° C. The reaction mixture was cooledto rt water (50 mL) and DCM (100 mL) were added. The organic layer wasseparated and aqueous layer was further extracted with DCM (2×50 mL).The pH of aqueous layer (˜11) was adjusted to pH9 with 2M HCl andre-extracted with DCM (2×100 mL). Organic layers at pH9 containing cleanproduct were combined, dried (Na₂SO₄) and concentrated to give theproduct (539 mg, 1.732 mmol, 30%) as a white solid. The first organicextractions at pH11 were combined, dried (Na₂SO₄) and concentrated togive 1.63 g of crude yellow oil. This was purified by chromatography onSiO₂ (100 g), eluting with 0-20% 2M NH₃ in MeOH/DCM over 1320 mL). Allfractions were mixed so fractions combined to give 1.53 g of crudeyellow oil. This was re-purified by chromatography on SiO₂ (50 g)eluting with 0-100% ethyl acetate/cyclohexane over 460 mL). Fractionscontaining desired product were concentrated to give the product (494mg, 1.587 mmol, 28%) as a white solid.

LCMS (2 min Formic): Rt=0.57 min, [MH]⁺=311, 313.

Intermediate 375:1-((2S,3R,4R)-6-bromo-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-4-amino-6-bromo-2-ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 374, 530 mg, 1.703 mmol),2-fluoropyrimidine (357 mg, 3.64 mmol) and DIPEA (1.190 mL, 6.81 mmol)in dimethyl sulfoxide (DMSO) (5 mL) was heated in a 5 mL microwave vialfor 4 h at 160° C. The reaction mixture partitioned between ethylacetate and sat. LiCl solution. The organic layer was separated, washedwith water, dried (Na₂SO₄) and concentrated to give 1.05 g crude yellowoil. This was purified by chromatography on SiO₂ (25 g) eluting with0-100% ethyl acetate/cyclohexane over 330 mL to give the product (571mg, 1.467 mmol, 86%) as a pale yellow solid. LCMS (2 min Formic):Rt=0.97 min, [MH]⁺=389, 391.

Intermediate 376: tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

1-((2S,3R,4R)-6-Bromo-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 375, 77 mg, 0.198 mmol), tert-butylpiperazine-1-carboxylate (60 mg, 0.322 mmol), Pd₂(dba)₃ (30 mg, 0.033mmol), DavePhos (30 mg, 0.076 mmol) and sodium tert-butoxide (57.0 mg,0.593 mmol) were combined in dry 1,4-dioxane (2 mL) in a 5 mL microwavevial. The reaction mixture was degassed for 15 mins and heated at 120°C. for 30 mins in the microwave. The reaction mixture was cooled to rtand filtered through celite (2.5 g cartridge) washing with ethylacetate. This was concentrated to give 210 mg of crude orange oil. Thiswas purified by chromatography on SiO₂ (10 g), eluting with 0-100% ethylacetate/cyclohexane over 120 mLs to give the product (55 mg, 0.111 mmol,56%) as a yellow oil.

LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=495.

Intermediate 377: tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

1-((2S,3R,4R)-6-bromo-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 375, 346 mg, 0.889 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(412 mg, 1.333 mmol), potassium carbonate (369 mg, 2.67 mmol) andPdCl₂P(Ph₃)₂ (64 mg, 0.091 mmol) were combined in a mixture of1,4-dioxane (3 ml) and water (1 ml) and heated in the microwave reactorat 120° C. for 40 min. The reaction mixture was diluted with ethylacetate and water. The organic layer was separated, washed with water,dried (Na₂SO₄) and concentrated to give ˜927 mg of crude brown residue.This was purified by chromatography on SiO₂ (50 g) eluting with 0-100%ethyl acetate/cyclohexane over 660 mL to give the product (352 mg, 0.716mmol, 81%) as a pale yellow oil. LCMS (2 min Formic): Rt=1.13 min,[MH]⁺=492.

Intermediate 378: tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a flask under nitrogen was added a sample of1-((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 371, 250 mg, 0.623 mmol). The samplewas dissolved in 1,4-dioxane (10 mL) and water (1.0 mL), and then tothis solution was added, with stirring, caesium carbonate (609 mg, 1.869mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(289 mg, 0.934 mmol) and palladium tetrakis (72.0 mg, 0.062 mmol). Themixture was heated, with stirring, at 80° C. under nitrogen for ˜1 h.The reaction mixture was allowed to stir at 80° C. for a total of 4 h.The reaction mixture was allowed to cool to rt, and diluted with ethylacetate and water. The layers were separated, and the aqueous layer wasextracted with further ethyl acetate. The organic layers were combinedand twice washed with brine. The organic layer was then dried oversodium sulphate, filtered and concentrated in vacuo to afford a darkbrown oil. This oil was taken up in dichloromethane, loaded onto a 50 gsilica flash column, and purified by flash silica gel chromatography—theproduct eluting in 60%-80% ethyl acetate in cyclohexane. The appropriatefractions were collected and concentrated in vacuo to afford thepurified product, (295.2 mg, 0.498 mmol, 80%). LCMS (2 min Formic):Rt=1.16 min, [MH]⁺=504.

Intermediate 379: tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxopiperazine-1-carboxylate

A solution of1-((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 371, 100 mg, 0.249 mmol), tert-butyl3-oxopiperazine-1-carboxylate (49.9 mg, 0.249 mmol),(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (3.85 μL, 0.025 mmol),copper(I) iodide (4.75 mg, 0.025 mmol) and K₂CO₃ (68.9 mg, 0.498 mmol)in 1,4-dioxane (4 mL) was stirred under nitrogen at 100° C. for 16 h.The reaction mixture was allowed to cool to rt, filtered through celiteand rinsed with ethyl acetate. The solution was concentrated in vacuoand the crude was dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified byMDAP (HpH). The appropriate fractions were combined and concentrated invacuo to give the product (40 mg, 0.077 mmol, 31%). LCMS (2 min Formic):Rt=0.92 min, [MH]⁺=521.

Intermediate 380: tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate

To a 2 mL-5 mL microwave vial was added samples of Pd₂(dba)₃ (22.82 mg,0.025 mmol), DavePhos (29.4 mg, 0.075 mmol), tert-butylpiperazine-1-carboxylate (46.4 mg, 0.249 mmol) and sodium tert-butoxide(35.9 mg, 0.374 mmol). To this was then added a sample of1-((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 371, 50 mg, 0.125 mmol), which hadbeen dissolved in 1,4-dioxane (2 mL). The vessel was sealed, and thesolution was degassed with nitrogen for ˜15 min. The vial was thenloaded into a microwave reactor, and heated at 120° C. for 30 min. Thereaction mixture was diluted with ethyl acetate, filtered through a 2.5g celite cartridge and concentrated in vacuo. The residue was taken upin dichloromethane, loaded onto a 10 g silica flash column, and purifiedby flash silica gel chromatography—the product eluting in 45%-100% ethylacetate/cyclohexane. The appropriate fractions were combined andconcentrated in vacuo to afford a yellow glass (16.1 mg, 0.022 mmol,18%). LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=507.

Intermediate 381: benzyl((2S,3R,4R)-1-acetyl-6-(1-benzyl-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

To a reaction vessel benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 219, 2.036 g, 4.45 mmol),1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.15 g, 4.05 mmol) and caesium carbonate (3.96 g, 12.14 mmol) wereadded in 1,4-dioxane (60 mL)/water (6 mL). The solution was degassedwith nitrogen and treated with palladium tetrakis (0.468 g, 0.405 mmol)before being degassed again with nitrogen and then it was left to stirat 80° C. for 16 h under nitrogen. The reaction solution was partitionedbetween water (80 mL) and ethyl acetate (80 mL) and the layersseparated. The aqueous phase was extracted with ethyl acetate (100 mL)and combined organics washed with brine soln. (80 mL) before beingconcentrated in vacuo to give 3.413 g of the crude product as a yellowfoam. This was purified by chromatography on SiO₂ (100 g) eluting with0-65% ethyl acetate/cyclohexane. The fractions containing product werecombined and concentrated in vacuo to give 1.643 g of the desiredproduct as a white solid.

LCMS (2 min Formic): Rt=1.17 min, [M-NH₂]⁺=535.

Intermediate 382:1-((2S,3R,4R)-4-amino-6-(1-benzyl-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Benzyl((2S,3R,4R)-1-acetyl-6-(1-benzyl-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 381, 1.643 g, 3.07 mmol) was takenup in tetrahydrofuran (THF) (25 mL), TBAF 1M in THE (9.4 mL, 9.40 mmol)was added and the solution was stirred under reflux for 5 h. TBAF 1M inTHE (3.07 mL, 3.07 mmol) was added and the reaction left to stir underreflux for 72 h. The reaction solution was partitioned between sat. aq.NaHCO₃ solution (80 mL) and DCM (80 mL), the aqueous phase was extractedwith a further 80 mL of DCM and the organics combined and dried througha hydrophobic frit before being concentrated in vacuo to give the crudeproduct as an orange/brown mixture. This was purified by chromatographyon SiO₂ (50 g) eluting with 0-4% 2 M ammonia in methanol/DCM. Thefractions containing product were combined and concentrated in vacuo togive 1.241 g of the desired product.

LCMS (2 min Formic): Rt=0.74 min, [M-NH₂]+=384.

Intermediate 383:1-((2S,3R,4R)-6-(1-benzyl-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a 2-5 ml microwave vial was added 2-chloro-4-methylpyrimidine (69.3mg, 0.539 mmol), potassium fluoride (39.2 mg, 0.674 mmol) and 18-crown-6(59.4 mg, 0.225 mmol), followed by a solution of1-((2S,3R,4R)-4-amino-6-(1-benzyl-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 382, 180 mg, 0.449 mmol) and DIPEA(0.133 mL, 0.764 mmol) in dimethyl sulfoxide (DMSO) (5 mL). The reactionvessel was sealed and heated to 160° C. for 4 h. Potassium fluoride(39.2 mg, 0.674 mmol), 18-crown-6 (59.4 mg, 0.225 mmol) and2-chloro-4-methylpyrimidine (46.2 mg, 0.360 mmol) were added and thereaction heated under microwave radiation to 160° C. for 2 h. Thereaction solution was partitioned between diethyl ether (40 mL) and andwater (40 mL). The layers were separated and the aqueous layer wasextracted with diethyl ether (2×40 mL). The organic layer was driedthrough a hydrophobic frit and concentrated in vacuo to give the crudeproduct as an orange oil. This was purified by chromatography on SiO₂(25 g) eluting with 0-100% ethyl acetate/cyclohexane. The fractionscontaining product were combined and concentrated in vacuo to give 133mg of the desired product as a pale yellow solid. LCMS (2 min Formic):Rt=1.05 min, [MH]⁺=493.

Intermediate 384: benzyl((2S,3S,4R)-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

4-Methoxyaniline (200 mg, 1.624 mmol) was taken up in DCM (7 mL) undernitrogen and cyclopropanecarbaldehyde (0.182 mL, 2.436 mmol) added. Thereaction was stirred at rt for 2 h with molecular sieves (25 g). Thereaction was cooled in an ice-bath for 10 min then (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 342 mg,1.786 mmol) in DCM (3 mL) was added. (11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see JACS, 2011, 133, 14804, 9.38 mg, 0.016mmol) was then added in one portion and the reaction left to stir for 16h. The reaction mixture was filtered and washed with DCM (10 mL), thenwashed with sat. NaHCO₃ (10 mL). The organic phase was filtered througha hydrophobic frit and evaporated in vacuo giving a white solid. Thesample was loaded in dichloromethane (1 mL) and purified on silica gel(25 g) cartridge using a 0-50% ethyl acetate-cyclohexane over 10 CV. Theappropriate fractions were combined and evaporated in vacuo to give therequired product (287.6 mg) as a white solid. Analysis by chiral HPLCwas undertaken using a 250×4.6 mm Chiralcel OJ column eluting with 25%ethanol in heptane at a flow rate of 1 mL/min. Peak 1/minor enantiomer(3% by UV) eluted at 9.6 min, and Peak 2/major enantiomer (97% by UV)eluted at 15.9 min. This indicated the product had an ee of >94%. LCMS(2 min HpH): Rt=1.21 min, [MH]⁺=367.

Intermediate 385: benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

A round bottom flask containing benzyl((2S,3S,4R)-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 384, 279.5 mg, 0.763 mmol) wassuspended in 2-methyltetrahydrofuran (2-MeTHF) (2 mL) under nitrogen.Acetyl chloride (0.163 mL, 2.288 mmol) was added to the mixture whichwas stirred at rt under nitrogen for 5 h. DIPEA (0.400 mL, 2.288 mmol)was then added and the reaction mixture stirred under nitrogen for 1 h.The reaction mixture was dissolved in ethyl acetate (5 mL) and asaturated solution of NaHCO₃ (10 mL) was then added. The phases wereseparated; the aqueous phase was extracted with ethyl acetate (5 mL).The organic phases were combined and further washed with NH₄Cl sat. (10mL). The organic phase was filtered through a hydrophobic frit andevaporated in vacuo giving the product (216 mg, 0.529 mmol, 69%) as awhite solid. LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=409.

Intermediate 386:1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-methoxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-methoxy-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 385, 216 mg, 0.529 mmol) in ethanol(5 mL) was added to 10 wt. % palladium on carbon (dry basis on activatedcarbon, wet, Degussa type E101 NE/W) (700 mg, 6.58 mmol) and the mixturestirred under an atmosphere of hydrogen at rt for 16 h. The reactionmixture was filtered through a EtOH-pre-conditioned 2 g celitecartridge, and the cartridge washed with EtOH (10 mL). The filtrate wasevaporated in vacuo and dried in a vacuum oven to give the product (122mg, 0.445 mmol, 84%) as a yellow solid.

LCMS (2 min Formic): Rt=0.53 min, [M-NH₂]⁺=258.

Intermediate 387:1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-S-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 344, 2 g, 4.37 mmol) was dissolvedin ethanol (25 mL) and 10% Pd/C 50% wet (0.2 g, 1.879 mmol) was added.The reaction mixture was hydrogenated for 25 h. The reaction mixture wasfiltered through celite (10 g) and washed with further ethanol (50 mL).The fractions were concentrated in vacuo to give a yellow solid (589mg).

LCMS (2 min Formic): Rt=0.49 min, [MH]⁺=245.

Intermediate 388:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(Pyrimidin-2-ylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

1-((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 371, 2.5474 g, 6.35 mmol) wasdissolved in dry dimethyl sulfoxide (DMSO) (20 mL).bis(pinacolato)diboron (3.22 g, 12.70 mmol), PdCl₂(dppf) (0.464 g, 0.635mmol) and potassium acetate (1.246 g, 12.70 mmol) were added andreaction mixture de-gassed under N₂. Reaction mixture was then heated at80° C. and stirred under N₂ for 16 h. The reaction mixture was cooled tort and partitioned between ethyl acetate and water. The bi-phasicmixture was passed through a celite cartridge. The organic and aqueouslayers were separated and the aqueous layer was extracted with moreethyl acetate (2×50 mL). The organic fractions were combined, dried bypassing through a hydrophobic frit and concentrated to give 7.1 g ofcrude brown residue. This was purified by chromatography (100 gcartridge, eluting with 10-70% ethyl acetate/cyclohexane over 10 CVs).Appropriate fractions were combined and the solvent removed in vacuo togive the product (2.98 g) as a brown glassy foam.

LCMS (2 min Formic): Rt=1.13 min, [MH]⁺=449.

Intermediate 389: rac-(2S,3S,4R)-methyl2-cyclopropyl-4-(phenylamino)-1,2,3,4-tetrahydroquinoline-3-carboxylate

A solution of aniline (1138 μL, 11.24 mmol) and methyl propiolate (500μL, 5.62 mmol) in ethanol (12 mL) was stirred at rt overnight.Cyclopropanecarbaldehyde (420 μL, 5.62 mmol), and4-methylbenzenesulfonic acid hydrate (267 mg, 1.405 mmol) were added andthe reaction stirred at rt for a further 6 h. A precipitate formedimmediately. The reaction was allowed to stir overnight. The reactionmixture was cooled to 0° C. and the precipitate was filtered off andwashed with cold ethanol to afford the product as a white solid (945 mg,2.93 mmol, 52%).

LCMS (2 min Formic): Rt=1.21 min, [M-NHPh]⁺=230.

Intermediate 390:rac-((2S,3S,4R)-2-cyclopropyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-3-yl)methanol

rac-(2S,3S,4R)-methyl2-cyclopropyl-4-(phenylamino)-1,2,3,4-tetrahydroquinoline-3-carboxylate(for a preparation see Intermediate 389, 736 mg, 2.283 mmol) wasdissolved in dichloromethane (DCM) (20 mL) and cooled in a dryice/acetone bath under nitrogen. 25% w/v DIBAL-H in toluene (2662 mg,4.68 mmol) was added drop-wise and the resulting solution stirred for 3h. Further 25% w/v DIBAL-H in toluene (2662 mg, 4.68 mmol) was added inone portion and the resulting solution stirred for 2 h. The reactionmixture was warmed to rt and TBME (20 mL) added. Water (0.4 mL),followed by 15% aq. NaOH (0.4 mL) and a subsequent portion of water(0.94 mL) were added and the reaction mixture stirred vigorously at 20°C. for 15 min. Copious MgSO₄ was added, the suspension stirred for 30min and allowed to stand overnight. The resulting suspension wasfiltered and the filtered solid washed with DCM. The filtrate wasevaporated to a pale yellow solid and redissolved in the minimum amountof DCM. The solution was loaded on to a 25 g SNAP silica column andeluted with cyclohexane:EtOAc (5->25%). The product containing fractionswere evaporated to a pale brown gum, redissolved in TBME and cyclohexaneand evaporated in vacuo to a white solid (591 mg). LCMS (2 min HpH):Rt=1.12 min, [M−H]⁺=293.

Intermediate 391: rac-(2S,3S,4R)-methyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

To a dry flask was added 3A molecular sieves (1 g), the flask wasevacuated and heated under vacuum to activate the molecular sieves. Theflask was backfilled with nitrogen and allowed to cool. A solution ofmethyl 4-amino-2-methoxybenzoate (1 g, 5.52 mmol) in dry DCM (37 mL),followed by cyclopropanecarbaldehyde (0.619 mL, 8.28 mmol) were added tothe reaction vessel under nitrogen and the resultant suspension stirredat rt for 1 h and then cooled to 0° C. Solutions of diphenyl hydrogenphosphate (0.069 g, 0.276 mmol) followed by (E)-benzylprop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 1.548 g,6.07 mmol) in dry DCM (2×7.5 mL) were added. The reaction was stirred at0° C. for 3 h and then allowed to warm to rt overnight. The reactionmixture was filtered, the residue was washed with MeOH (2×50 mL) andEtOAc (25 mL) into a separate flask to the initial filtrate. The DCMfiltrate was concentrated in vacuo to give the product as a yellow solid(2.44 g, 2.87 mmol, 52%-only ˜50% pure). The MeOH/EtOAc washings werealso concentrated in vacuo to leave the product as a white solid (239mg, 0.563 mmol, 10%). The solid residue was also collected and providedfurther product as a beige solid (1.44 g, 3.39 mmol, 62%).

LCMS (2 min Formic): Rt=1.13 min, [MH]⁺=425.

Intermediate 392: rac-(2S,3R,4R)-methyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

rac-(2S,3S,4R)-Methyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 391, 2.44 g, 2.87 mmol) was taken upin dichloromethane (DCM) (25 mL) and treated with DIPEA (2.008 mL, 11.50mmol) and acetyl chloride (1.022 mL, 14.37 mmol) and allowed to stir atrt for 1 h. Water (30 mL) was added and further DCM (20 mL) and thelayers separated. The aqueous layer was further extracted with DCM (2×40mL) and the organics combined. This was dried (Na₂SO₄) and concentratedin vacuo to afford the crude product as a yellow oil. This was taken upin DCM and added to a 100 g silica cartridge and purified by flashchromatography, eluting with 20%->100% EtOAc/cyclohexane. Theappropriate fractions were collected and concentrated in vacuo to affordthe desired product as a white foam (1.27 g, 2.72 mmol, 95%). LCMS (2min Formic): Rt=1.05 min, [MH]⁺=467.

Intermediate 393: rac-(2S,3R,4R)-methyl1-acetyl-4-amino-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A conical flask was charged with rac-(2S,3R,4R)-methyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 392, 1.27 g, 2.72 mmol), ethanol (53mL) and 10% palladium on carbon (0.116 g, 1.089 mmol). The reactionmixture was stirred under an atmosphere of hydrogen for ˜24 h. Thereaction mixture was filtered through celite and eluted with ethanol(2×20 mL). The filtrate was concentrated in vacuo to give a yellow oil.This was taken up in DCM and added to a 100 g silica column, this waspurified by flash chromatography, eluting with 0%->20% (20% (2M NH₃ inMeOH)/DCM)/DCM. The appropriate fractions were combined and concentratedin vacuo to afford the desired product as a yellow solid (628 mg, 1.889mmol, 69%). LCMS (2 min Formic): Rt=0.50 min, [M-NH₂]+=316.

Intermediate 394:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

rac-(2S,3R,4R)-Methyl1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 393, 85 mg, 0.200 mmol) was taken upin tetrahydrofuran (THF) (870 μL) and water (870 μL). Lithium hydroxide(11.99 mg, 0.501 mmol) was added and the reaction stirred for 16 h atrt. 2M HCl (aq) (250 μL, 0.501 mmol) was added followed by 10% MeOH/DCM(20 mL) and water (20 mL). The biphasic mixture was stirred for 5 minand the layers then separated. The aqueous layer was further extractedwith 10% MeOH/DCM (2×20 mL). The combined organics were collected, dried(Na₂SO₄) and concentrated in vacuo to afford the desired product as ayellow solid (82 mg, 0.200 mmol, 100%). LCMS (2 min Formic): Rt=0.70min, [MH]⁺=411.

Intermediate 395: (2S,3S,4R)-methyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-5-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate& (2S,3S,4R)-methyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(˜1:1)

A solution of methyl 4-amino-2-fluorobenzoate (1 g, 5.91 mmol) andcyclopropanecarbaldehyde (0.663 mL, 8.87 mmol) in dry DCM (37 mL) wasstirred in a reaction vessel under nitrogen at room temperature for 1hour and then cooled to 0° C. Solutions of (11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide (for a preparation see for a preparation see JACS, 2011, 133,14804, 0.034 g, 0.059 mmol) followed by (E)-benzylprop-1-en-1-ylcarbamate (fora preparation see Intermediate 1, 1.244 g,6.50 mmol) in dry DCM (2×7.5 mL) were added. The reaction was stirred at0° C. for 3 h and then allowed to warm to rt overnight. The reactionmixture was filtered and the filtrate was concentrated in vacuo toafford the crude product as a beige solid (1.059 g, 1.284 mmol, 43.4%yield). The residue was also collected to give further product as awhite solid (1.456 g, 1.765 mmol, 60%).

LCMS (2 min Formic): Rt=1.18 min, [MH]⁺=413.

Intermediate 396: (2S,3R,4R)-methyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

(2S,3S,4R)-methyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-5-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylatecompound & (2S,3S,4R)-methyl4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(˜1:1) (for a preparation see Intermediate 395, 403 mg, 0.489 mmol) wastaken up in dichloromethane (DCM) (10 mL) and treated with acetylchloride (0.139 mL, 1.954 mmol) and allowed to stir at rt for 58 h.Further acetyl chloride (0.139 mL, 1.954 mmol) was added and thereaction allowed to stir for ˜3 h. The reaction was diluted with DCM (20mL) and 2M HCl(aq) (20 mL) and the layers separated. The aqueous layerwas washed with further DCM (2×20 mL) and the combined organics werethen washed with NaHCO₃ (aq) solution (20 mL), dried (Na₂SO₄) andconcentrated in vacuo. As the product still contained a significantimpurity, the crude was further purified by MDAP (HpH) to give theproduct (116 mg, 0.255 mmol, 26%). LCMS (2 min Formic): Rt=1.10 min,[MH]⁺=455.

Intermediate 397: (2S,3R,4R)-methyl1-acetyl-4-amino-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate

A conical flask was charged with (2S,3R,4R)-methyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 396, 235 mg, 0.517 mmol), ethanol(10 mL) and 10% palladium on carbon (22.01 mg, 0.207 mmol). The reactionmixture was stirred under an atmosphere of hydrogen for ˜16 h. Thereaction mixture was filtered through celite and eluted with ethanol(2×20 mL). The filtrate was concentrated in vacuo to give a yellow oilMDAP (HpH) to afford the product (40 mg, 0.125 mmol, 24%) as acolourless gum. LCMS (2 min Formic): Rt=0.57 min, [M-NH₂]⁺=304.

Intermediate 398: (2S,3R,4R)-methyl1-acetyl-2-cyclopropyl-7-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate

A solution of 2-chloro-4-methylpyrimidine (48.2 mg, 0.375 mmol),potassium fluoride (32.6 mg, 0.562 mmol), (2S,3R,4R)-methyl1-acetyl-4-amino-2-cyclopropyl-7-fluoro-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 397, 40 mg, 0.125 mmol), 18-crown-6(49.5 mg, 0.187 mmol) and DIPEA (0.109 mL, 0.624 mmol) in DimethylSulfoxide (DMSO) (0.7 mL) was added to a microwave vial and the vialsealed and heated to 160° C. for 2 h. The reaction mixture waspartitioned between water and Et₂O. The layers were separated and theaqueous layer further extracted with Et₂O. The combined organics wereback extracted with water, dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by Silica gel column chromatography elutingwith a gradient of 25 to 100% EtOAc/cyclohexane to give the product(21.9 mg, 0.053 mmol, 43%) as a yellow solid. LCMS (2 min Formic):Rt=0.92 min, [MH]⁺=413.

Intermediate 399:(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Methyl1-acetyl-2-cyclopropyl-7-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 398, 21.9 mg, 0.053 mmol) was takenup in tetrahydrofuran (THF) (1 mL) and water (1000 μL). lithiumhydroxide (6.36 mg, 0.265 mmol) was added and the reaction stirred for˜1 h at rt. 2M HCl(aq) (150 μL, 0.300 mmol) was added, followed by 10%MeOH/DCM and water. The layers were separated and the aqueous layer wasfurther extracted with 10% MeOH/DCM and DCM. The combined organics weredried (Na₂SO₄) and concentrated in vacuo to afford the crude product asa yellow oil (19.7 mg, 0.049 mmol, 93%). LCMS (2 min Formic): Rt=0.75min, [MH]⁺=399

Intermediate 400: rac-benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-8-methoxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-4-yl)carbamate

To a solution of 6-bromo-2-methoxypyridin-3-amine (3.10 g, 15.27 mmol)in 2-Me THE (30 mL) was added cyclopropanecarbaldehyde (2.30 mL, 30.8mmol). The mixture was stirred in a stoppered vessel at rt for 1 h. Tothe solution was added ytterbium(III) triflate (9.50 g, 15.32 mmol)followed by (E)-benzyl prop-1-en-1-ylcarbamate (for a preparation seeIntermediate 1, 3.10 g, 16.21 mmol) and the mixture stirred at rt for 4h. The reaction mixture was evaporated under vacuum and the foam/gum waspartially dissolved in DCM (100 mL) and washed with water (3×100 mL).The organic layer was dried through a hydrophobic frit and the solventremoved by rotary evaporation to give the product as a light brown solid(6.80 g, 15.24 mmol, 100%, 76% pure).

LCMS (2 min HpH): Rt=1.37 min, [MH]⁺=446, 448.

Intermediate 401: rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-8-methoxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-4-yl)carbamate

A solution of rac-benzyl((2S,3S,4R)-6-bromo-2-cyclopropyl-8-methoxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 400, 6.80 g, 15.24 mmol) in aceticanhydride (50 ml, 530 mmol) was stirred at 100° C. for 20 h. Thereaction mixture was allowed to cool to rt and diluted with EtOAc (50mL). The organic layer was stirred vigorously with 1 M NaOH (aq) (50mL), separated and the processed repeated twice. The organic layer waswashed with water (50 mL), dried through a hydrophobic frit and thesolvent evaporated under vacuum. The residue was dissolved in DCM (20mL), applied to a 340 g silica cartridge and purified using a gradientof 0-100% EtOAc in cyclohexane over 8 CVs. The appropriate fractionswere combined and the solvent removed by rotary evaporation to give theproduct as a light brown foam (4.77 g, 9.77 mmol, 64%). LCMS (2 minFormic): Rt=1.19 min, [MH]⁺=488, 490.

Intermediate 402: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-8-methoxy-3-methyl-6-morpholino-1,2,3,4-tetrahydro-1,7-naphthyridin-4-yl)carbamate

To a mixture of sodium tert-butoxide (0.550 g, 5.72 mmol), Pd₂(dba)₃(0.200 g, 0.218 mmol), Dave Phos (0.160 g, 0.407 mmol), rac-benzyl((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-8-methoxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 401, 2.15 g, 4.40 mmol) in anhydrous1,4-dioxane (25 mL) was added morpholine (0.42 mL, 4.82 mmol) and themixture stirred at 100° C. under nitrogen for 3 h. The reaction mixturewas filtered through celite and the cake washed with EtOAc (50 mL). Thefiltrate was evaporated under vacuum and the residue dissolved in DCM (5mL). The solution was loaded onto a silica cartridge and purified usinga gradient of 0-60% EtOAc in DCM over 10 CVs. The appropriate fractionswere combined and the solvent removed by rotary evaporation to give theproduct as a light brown foam (1.09 g, 2.204 mmol, 50%). LCMS (2 minFormic): Rt=1.10 min, [MH]⁺=495.

Intermediate 403:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-8-methoxy-3-methyl-6-morpholino-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

A solution of rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-8-methoxy-3-methyl-6-morpholino-1,2,3,4-tetrahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 402, 1.05 g, 2.123 mmol) in ethanol(15 mL) was added to 10 wt. % palladium on carbon (dry basis) onactivated carbon (wet, Degussa type E101 NE/W) (110 mg, 1.034 mmol) andthe mixture stirred under an atmosphere of hydrogen at rt for 16 h. Thereaction mixture was filtered through celite and the cake washed withEtOH (80 mL). The filtrate was evaporated in vacuo and the residue driedin a high-vacuum oven to give the product as a yellow solid (746 mg,2.070 mmol, 97%).

LCMS (2 min HpH): Rt=0.86 min, [MH]⁺=361.

Intermediate 404:rac-1-((2S,3R,4R)-2-cyclopropyl-8-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

A mixture of sodium tert-butoxide (144 mg, 1.494 mmol), Pd₂(dba)₃ (45.6mg, 0.050 mmol), Dave Phos (39.2 mg, 0.100 mmol) andrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-8-methoxy-3-methyl-6-morpholino-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 403, 359 mg, 0.996 mmol). Themixture was diluted with anhydrous 1,4-dioxane (5 mL) and treated with2-bromo-6-methylpyridine (0.136 mL, 1.195 mmol). The vessel wasevacuated, purged with nitrogen and stirred under nitrogen at 100° C.for 4 h. The reaction mixture was filtered through celite and the cakewashed with EtOAc (40 mL). The filtrate was evaporated under vacuum andthe residue dissolved in MeOH (5 mL). The solution was applied to a 20 gSCX-2 cartridge and the cartridge washed with MeOH (120 mL) followed by2 M NH₃ in MeOH (120 mL). The basic wash was evaporated in vacuo, theresidue loaded in DCM (4 mL) and purified on a 100 g silica cartridgeusing a gradient of 0-100% EtOAc (+1% NEt₃) in DCM (+1% NEt₃) over 10CVs. The appropriate fractions were combined and the solvent removed byrotary evaporation to give the product (445 mg) as an orange gum. Thecompound not completely pure but was used as was in further chemistry.

LCMS (2 min Formic): Rt=0.71 min, [MH]⁺=452.

Intermediate 405:rac-1-((2S,3R,4R)-2-cyclopropyl-8-hydroxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-2-cyclopropyl-8-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 404, 358 mg, 0.793 mmol) and sodiumiodide (713 mg, 4.76 mmol) was diluted with acetonitrile (1 mL) andTMSCl (0.608 mL, 4.76 mmol) was added. The mixture was stirred undernitrogen at 55° C. for 3 h. The reaction solution was allowed to cool rtand evaporated under vacuum. The residue was suspended in EtOAc (25 mL)and washed sequentially with saturated aqueous NaHCO₃ (2×25 mL) andwater (25 mL). The organic layer was dried through a hydrophobic fritand the solvent removed under vacuum. The residue was loaded in DCM (5mL) and purified on a 100 g silica cartridge using a gradient of 0-15%MeOH in DCM over 10 CVs. The appropriate fractions were combined and thesolvent removed by rotary evaporation to give the product as a darkgreen glass (84 mg, 0.192 mmol, 24%). LCMS (2 min Formic): Rt=0.48 min,[MH]⁺=438.

Intermediate 406:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate

A solution ofrac-1-((2S,3R,4R)-2-cyclopropyl-8-hydroxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 405, 84 mg, 0.192 mmol) in DCM (1mL) was treated with triethylamine (0.054 mL, 0.384 mmol), DMAP (2 mg,0.016 mmol) andN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(94 mg, 0.240 mmol). The mixture was stirred at rt in a stoppered vesselfor 64 h. The reaction mixture was diluted with DCM (4 mL) and washedwith water (3×5 mL). The organic layer was dried through a hydrophobicfrit and concentrated in vacuo. The brown gum was loaded in DCM (2 mL)and purified on a 25 g silica cartridge using a gradient of 0-15% 2MNH₃/MeOH in DCM over 10 CVs. The appropriate fractions were combined andthe solvent removed by rotary evaporation. The gum was purified by MDAP(HpH). The appropriate fractions were combined and the solvent removedby rotary evaporation to give the product as a purple foam (52 mg, 0.091mmol, 48%). LCMS (2 min HpH): Rt=1.27 min, [MH]⁺=570.

Intermediate 407:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-1,2,3,4-tetrahydro-1,7-naphthyridin-8-yltrifluoromethanesulfonate (for a preparation see Intermediate 406, 50mg, 0.088 mmol) and Pd(dppf)Cl₂ (10 mg, 0.012 mmol) in anhydrous DMF (1mL) was treated with triethylamine (50 μL, 0.359 mmol) and formic acid(10 μL, 0.261 mmol) and the mixture stirred under nitrogen at 60° C. for1 h. Further Pd(dppf)Cl₂ (10 mg, 0.012 mmol) was added and the mixturestirred under nitrogen at 60° C. for 15 h. Further formic acid (20 μL,0.522 mmol) was added and the mixture stirred under nitrogen at 100° C.for 5 h. Further formic acid (20 μL, 0.522 mmol) and Pd(dppf)Cl₂ (10 mg,0.012 mmol) was added and the mixture stirred under nitrogen at 100° C.for 15 h. The reaction mixture was allowed to cool to rt and applieddirectly to a MeOH-preconditioned 2 g SCX-2 cartridge. The cartridge waswashed with MeOH (10 mL) followed by 2 M NH₃ in MeOH solution (10 mL).The basic wash was concentrated under vacuum and the residue purified byMDAP (HpH). The appropriate fractions were combined and concentrated invacuo to give the product as an off-white solid (22 mg, 0.052 mmol,60%).

LCMS (2 min HpH): Rt=1.00 min, [MH]⁺=422.

Intermediate 408: rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-8-methoxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate

A solution of benzylrac-((2S,3R,4R)-1-acetyl-6-bromo-2-cyclopropyl-8-methoxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-4-yl)carbamate(for a preparation see Intermediate 401, 4.96 g, 10.16 mmol), Et₃N(14.16 mL, 102 mmol) and Pd(PPh₃)₄ (2.93 g, 2.54 mmol) in 1,4-dioxane(50 mL) and ethanol (50 mL) was made up in a 3 necked round bottom flaskunder nitrogen and the flask was purged with carbon monoxide for 1 h at80° C. The reaction mixture was stirred under an atmosphere of carbonmonoxide (balloon filled with carbon monoxide) at 80° C. After 6.5 h theballoon was refilled and reaction mixture was stirred at 80° C. for 17h. Carbon monoxide was bubbled through the solution for 1 h at 80° C.The reaction mixture was allowed to cool to rt. The reaction mixture wasconcentrated under reduced pressure, the residue was partitioned betweenDCM (100 mL) and water (100 mL). The organic layer was dried throughhydrophobic frit and concentrated under reduced pressure. The residue(9.8 g) was loaded on 2×100 g silica cartridges, purified by columnchromatography, eluting with 10-40% EtOAc in cyclohexane (20 CV). Theappropriate fractions were combined and concentrated under reducedpressure to give 2 batches of desired product (1.94 g, 4.03 mmol, 40%)as a colourless oil; (2.06 g, 4.28 mmol, 42%) as a brown solid. LCMS (2min HpH): Rt=1.14 min, [MH]⁺=482.

Intermediate 409: rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-8-hydroxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate

TMSCl (0.256 mL, 2.014 mmol) and sodium iodide (0.302 g, 2.014 mmol)were added to a solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-8-methoxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate(for a preparation see Intermediate 408, 1.94 g, 4.03 mmol) inacetonitrile (50 mL). After stirring at rt for 6 h the reaction mixturewas concentrated under reduced pressure. The residue was taken up inEtOAc (100 mL), quenched with a saturated solution of sodium bicarbonate(100 mL). The organic layer was separated and the aqueous layer wasextracted with EtOAc (100 mL). The combined organic layer was driedthrough hydrophobic frit and concentrated under reduced pressure. Theresidue (2.05 g) was loaded on a 100 g silica cartridge, purified bycolumn chromatography, eluting with 0-10% MeOH in DCM (20 CV). Theappropriate fractions were combined and concentrated under reducedpressure to give the required product (1.6 g) as a colourless oil. LCMS(2 min HpH): Rt=0.93 min, [MH]⁺=468.

Intermediate 410: rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-8-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate

A solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-8-hydroxy-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate(for a preparation see Intermediate 409, 1.6 g, 3.42 mmol) in DCM (50mL) was cooled with an ice bath. Triethylamine (0.954 mL, 6.84 mmol),DMAP (0.084 g, 0.684 mmol) andN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.680 g, 4.28 mmol) were added. The mixture was stirred at rt undernitrogen for 18 h. Triethylamine (0.954 mL, 6.84 mmol), DMAP (0.084 g,0.684 mmol) andN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.680 g, 4.28 mmol) were added. After stirring for 1 h. the reactionmixture was diluted with DCM (50 mL) and washed with water (2×100 mL).The organic layer was dried through a hydrophobic frit and concentratedin vacuo. The residue was loaded in DCM on a 100 g silica cartridge andeluted using a gradient of 10-60% EtOAc in cyclohexane (15 CV). Theappropriate fractions were combined and concentrated under reducedpressure to give the required product (1.69 g) as a yellow oil.

LCMS (2 min HpH): Rt=1.30 min, [MH]⁺=600.

Intermediate 411: rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate

A solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-(((benzyloxy)carbonyl)amino)-2-cyclopropyl-3-methyl-8-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate(for a preparation see Intermediate 410, 600 mg, 1.001 mmol) and Pd/C(368 mg, 3.46 mmol) in ethanol (30 mL) was hydrogenated at rt. After 20h of stirring at rt, the reaction mixture was filtered through celiteand concentrated under reduced pressure. The residue (474 mg) was loadedon a 50 g silica column in MeOH/DCM 1:3 which was then dried in thevacuum oven for 20 min. The purification was carried out by columnchromatography, eluting with 0-5% methanolic ammonia (2M) in DCM (15CV). The appropriate fractions were combined and concentrated underreduced pressure to give the required product (153 mg) as a yellow oil.LCMS (2 min HpH): Rt=0.70 min, [MH]⁺=318.

Intermediate 412: rac-(2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate

DIPEA (0.080 mL, 0.457 mmol) and 2-fluoropyrimidine (49.3 mg, 0.503mmol) were added to a solution of rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate(for a preparation see Intermediate 411, 145 mg, 0.457 mmol) in dimethylsulfoxide (DMSO) (0.2 mL) in a microwave vessel. The vessel was sealedand heated at 120° C. for 19 h. The reaction mixture was partitionedbetween EtOAc (40 mL) and water (40 mL). The organic layer was furtherwashed with water (40 mL) and brine (2×40 mL). The organic layer wasdried through a hydrophobic frit and concentrated under reducedpressure. The residue (164 mg) was loaded on a 25 g silica column,purified by column chromatography, eluting with a gradient of 0-8% MeOHin DCM (15 CV). The appropriate fractions were combined and evaporatedin vacuo to give the required product (124 mg) as a yellow oil. LCMS (2min HpH): Rt=0.84 min, [MH]⁺=396.

Intermediate 413:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylicacid

Lithium hydroxide. H₂O (26 mg, 0.620 mmol) was added to a solution ofrac-(2S,3R,4R)-ethyl1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylate(for a preparation see Intermediate 412, 120 mg, 0.303 mmol) in amixture of tetrahydrofuran (THF) (3 mL) and water (1 mL). After stirringat rt for 5 h the reaction mixture was concentrated under reducedpressure. The residue was taken up in water (20 mL), cooled with an icebath and acidified with aqueous HCl (0.310 mL, 0.620 mmol). The aqueoussolution was extracted with EtOAc (2×20 mL) and 20% MeOH in DCM (2×50mL). The organic layers were combined, dried through hydrophobic fritand concentrated under reduced pressure to give the required product (97mg) as a yellow solid. LCMS (2 min Formic): Rt=0.61 min, [MH]⁺=368.

Intermediate 414: rac-benzyl((2S,3S,4R)-2-cyclopropyl-5-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate& benzyl((2S,3S,4R)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate(˜1:1)

The 2-methoxypyridin-4-amine (1 g, 8.06 mmol) was taken up intetrahydrofuran (THF) (10 mL) and was treated withcyclopropanecarbaldehyde (0.721 mL, 9.67 mmol) and allowed to stir at rtfor 1 h. (E)-benzyl prop-1-en-1-ylcarbamate (for a preparation seeIntermediate 1, 1.694 g, 8.86 mmol) and ytterbium(III)trifluoromethanesulfonate (2.498 g, 4.03 mmol) were added and thereaction allowed to stir at 65° C. for ˜24 h. The reaction was allowedto cool and was concentrated and partitioned between water and EtOAc,the organic layer was washed with NaHCO₃(aq), dried using a hydrophobicfrit and concentrated to a gum. This gum was purified using a 100 gcolumn elute 0-50% EtOAc:cyclohexane the appropriate fractions weresummed and concentrated to give what was believed to be a mixture of thetitle compounds (1.855 g, 2.52 mmol, 31%) as a white solid.

LCMS (2 min Formic): Rt=0.81, 0.83 min, [MH]⁺=368.

Intermediate 415: rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-5-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate& benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate(˜1:1)

The rac-benzyl((2S,3S,4R)-2-cyclopropyl-5-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate& benzyl((2S,3S,4R)-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate(˜1:1) (for a preparation see Intermediate 414, 1.855 g, 2.52 mmol) wastaken up in acetic anhydride (20 ml, 212 mmol) and allowed to stir at50° C. for 16 h. The reaction was allowed to stir at 100° C. for 3 h.The reaction was allowed to stir at 120° C. for 6 h. The reaction wasallowed to stir at 80° C. overnight and then at 110° C. for 5 h. Thereaction was allowed to cool to rt and was concentrated and purifiedusing a 50 g silica column elute 0-50% EtOAc:cyclohexane. Theappropriate fractions were summed and concentrated to give what wasbelieved to be a mixture of the title compounds (1.512 g, 1.846 mmol,73%) as a yellow solid.

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=410.

Intermediate 416:rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-5-methoxy-3-methyl-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone&1-((2S,3R,4R)-4-amino-2-cyclopropyl-7-methoxy-3-methyl-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(˜1:1)

The rac-benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-5-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate& benzyl((2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-yl)carbamate(˜1:1) (for a preparation see Intermediate 415, 1.5 g, 1.832 mmol) wastaken up in ethanol (20 mL) and treated with 10% Pd/C (150 mg, 1.410mmol) and allowed to stir under a atmosphere of hydrogen for 3 h. Thereaction was filtered through celite to remove catalyst and wasconcentrated to a yellow gum. This gum was purified using a 50 g silicacolumn elute 0-10% 2M NH₃/MeOH:DCM, the appropriate fractions weresummed and concentrated to give what was believed to be a mixture of thetitle compounds (685 mg, 1.244 mmol, 68%) as a yellow gum. LCMS (2 minFormic): Rt=0.47 & 0.57 min, [MH]⁺=276.

Intermediate 417:rac-1-((2S,3R,4R)-2-cyclopropyl-5-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone&1-((2S,3R,4R)-2-cyclopropyl-7-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(˜1:1)

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-5-methoxy-3-methyl-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone&1-((2S,3R,4R)-4-amino-2-cyclopropyl-7-methoxy-3-methyl-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(˜1:1) (for a preparation see Intermediate 416, 675 mg, 1.226 mmol),2-chloro-4-methylpyrimidine (189 mg, 1.471 mmol), 18-crown-6 (162 mg,0.613 mmol), potassium fluoride (107 mg, 1.839 mmol), DIPEA (0.364 mL,2.084 mmol) and dimethyl sulfoxide (DMSO) (20 mL) were all placed in amicrowaveable vial and irradiated at 160° C. for 4 h. The reaction wastreated with further 2-chloro-4-methylpyrimidine (60 mg, 0.467 mmol) andirradiated in microwave at 160° C. for 1 h. The reaction was dilutedwith water and extracted with EtOAc (×2) the combined organics werewashed with 10% LiCl(aq) and dried using a hydrophobic frit andconcentrated to a gum. This gum was purified using a 25 g silica column,elute 0-100% EtOAc:cyclohexane, the appropriate fractions were summed,concentrated and dried to give what was believed to be a mixture of thetitle compounds (420 mg, 0.572 mmol, 47%) as a buff solid.

LCMS (2 min Formic): Rt=0.77 & 0.80 min, [MH]⁺=368.

Intermediate 418:rac-1-((2S,3R,4R)-2-cyclopropyl-5-hydroxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone&1-((2S,3R,4R)-2-cyclopropyl-7-hydroxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(˜1:1)

Therac-1-((2S,3R,4R)-2-cyclopropyl-5-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone&1-((2S,3R,4R)-2-cyclopropyl-7-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(˜1:1) (for a preparation see Intermediate 417, 420 mg, 0.572 mmol) wassuspended in acetonitrile (5 mL) and was treated with sodium iodide (514mg, 3.43 mmol) followed by TMSCl (0.438 mL, 3.43 mmol), the resultingsuspension was allowed to stir at 55° C. for 2 h. The reaction wasconcentrated and partitioned between water and EtOAc, the organic layerwas separated and the aqueous phase extracted with further EtOAc, thecombined organics were washed with NaHCO₃(aq), dried using a hydrophobicfrit and concentrated to a yellow solid. This solid was purified using a25 g silica column elute: 0-15% MeOH:DCM. The appropriate fractions weresummed and concentrated to give what was believed to be a mixture of thetitle compounds (213 mg, 0.301 mmol, 53%) as an orange glass.

LCMS (2 min Formic): Rt=0.58 & 0.59 min, [MH]⁺=354.

Intermediate 419:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-yltrifluoromethanesulfonate &(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yltrifluoromethanesulfonate (˜1:1)

Therac-1-((2S,3R,4R)-2-cyclopropyl-5-hydroxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone&1-((2S,3R,4R)-2-cyclopropyl-7-hydroxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(˜1:1) (for a preparation see Intermediate 418, 210 mg, 0.297 mmol) wastaken up in dichloromethane (DCM) (5 mL) and was treated withtriethylamine (0.083 mL, 0.594 mmol), DMAP (3.63 mg, 0.030 mmol) andN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(152 mg, 0.386 mmol) and allowed to stir at rt under nitrogen for 20 h.The reaction was treated with furtherN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(58.3 mg, 0.149 mmol) and allowed to stir at rt for 24 h. The reactionwas treated with furtherN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(58.3 mg, 0.149 mmol) and triethylamine (0.041 mL, 0.297 mmol) andallowed to stir at rt for 3 h. The reaction was diluted with DCM andwashed with water, the organic phase was dried through a hydrophobicfrit and concentrated to a gum. This gum was purified using a 25 gsilica column elute: 0-100% EtOAc:cyclohexane, the appropriate fractionswere summed and concentrated to give 271 mg of a yellow solid, This wasfurther purified using a MDAP (HpH). The appropriate fractions weresummed and concentrated and dried to give what was believed to be amixture of the title compounds (133 mg, 0.137 mmol, 46%) yellow solid.LCMS (2 min Formic): Rt=1.11 & 1.13 min, [MH]⁺=486.

Intermediate 420: rac-benzyl((2S,3R,4R)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-ylcarbamate

Cyclopropanecarboxaldehyde (0.080 ml, 1.074 mmol) was added to a stirredsolution of aniline (0.098 ml, 1.074 mmol) in toluene (8 mL) under N₂,over 3A molecular sieves (1.0 g) at rt for 3 h and cooled in acyclohexane:dry ice bath. The reaction mixture was allowed to warm toroom temperature overnight and cooled in an acetone:dry ice bath.(2)-benzyl prop-1-en-1-ylcarbamate (for a preparation see JACS, 2013,135, 16010, 0.246 g, 1.289 mmol) dissolved in toluene (1 mL) was added,followed by BF₃.OEt₂ (0.136 ml, 1.074 mmol) and the cold bath removed.The reaction mixture was stirred for 1 h. The reaction mixture waspartitioned between DCM and water. The organic layer was removed, theaqueous portion extracted with DCM, the organic portions combined, driedover MgSO₄ and evaporated in vacuo to a brown oil. The residue wasdissolved in DCM (10 mL) and cyclohexane (10 mL) added. The resultingsuspension was loaded on to a 25 g silica column and eluted withcyclohexane:DCM (25-100%). The first eluting fractions contained impuredesired product. The following fractions contained the rac-(2S,3S,4R)isomer (47 mg). The final eluting product was impure rac-(2S,3R,4S)isomer (45 mg). The impure desired material was purified by MDAP (TFA).Evaporation of the desired fraction gave the product as a pale greensolid (150 mg). LCMS (2 min TFA): Rt=1.03 min, [MH]⁺=337.

Intermediate 421: rac-benzyl((2S,3S,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

Acetyl chloride (0.063 mL, 0.892 mmol) was added to a stirred solutionof pyridine (0.108 mL, 1.338 mmol) and rac-benzyl((2S,3R,4R)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 420, 150 mg, 0.446 mmol) indichloromethane (DCM) (5 mL) under N₂. The resulting solution wasstirred for 2.5 h. The reaction mixture was partitioned between EtOAcand aq. sat. NaHCO₃. The aqueous layer was removed, the organic layerwashed (1× aq. sat. NaHCO₃, 1× brine), dried over MgSO₄ and evaporatedin vacuo to a green gum. The residue was dissolved in DCM, loaded on toa 10 g silica column and eluted with cyclohexane:EtOAc (5-33%). Theproduct containing fractions were evaporated in vacuo to a colourlessgum (95 mg).

LCMS (2 min TFA): Rt=1.11 min, [MH]⁺=379.

Intermediate 422:rac-1-((2S,3S,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A suspension of rac-benzyl((2S,3S,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate(for a preparation see Intermediate 421, 95 mg, 0.251 mmol) and 10% Pd/C(26.7 mg, 0.025 mmol) was stirred in ethanol (6 mL) under hydrogen for 5h. The resulting suspension was filtered through celite and evaporatedin vacuo to a colourless oil (58 mg).

LCMS (2 min TFA): Rt=0.56 min, [M-NH₂]+=228.

Example 1:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Under nitrogen atmosphere, to a solution of bromobenzene (0.04 mL, 0.380mmol) in 1,4-dioxane (3 mL) were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 6, 69 mg, 0.317mmol), DavePhos (12 mg, 0.032 mmol),tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.016 mmol) and sodiumtert-butoxide (46 mg, 0.475 mmol). The reaction was degassed withnitrogen for 10 min. Using a microwave reactor the solution was stirredand irradiated with microwaves so as to maintain a temperature of 110°C. for 30 min. The solution was transferred into another 2-5 mLmicrowave vial via syringe, bromobenzene (0.04 mL, 0.380 mmol),tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.016 mmol), DavePhos(12 mg, 0.032 mmol) and sodium tert-butoxide (46 mg, 0.475 mmol) wereadded, the reaction mixture was degassed with nitrogen for 10 min, thenstirred and irradiated with microwaves so as to maintain a temperatureof 110° C. for 30 min. After cooling to rt, the reaction mixture wasfiltered through a pad of celite (rinsed with EtOAc). The filtrate wasthen evaporated in vacuo. The residue was loaded onto a 25 g silicacartridge and purified by column chromatography using a gradient of0-40% ethyl acetate in cyclohexane. Desired fractions were combined andevaporated in vacuo to afford the product as a yellow solid (26 mg).

LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=295.

Example 2:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 44 mg, 0.20 mmol),2-chloro-6-methylpyridine (0.02 mL, 0.24 mmol),tris(dibenzylideneacetone)dipalladium(0) (9 mg, 9.99 μmol), sodiumtert-butoxide (29 mg, 0.30 mmol), DavePhos (8 mg, 0.02 mmol) and1,4-dioxane (2.5 mL). The reaction mixture was then heated and stirredat 100° C. in a greenhouse reactor for 3 h. After cooling to rt, thereaction mixture was filtered through a pad of celite (rinsed withEtOAc). The filtrate was then evaporated in vacuo. The residue waspurified by MDAP (Formic) chromatography. Desired fractions werecombined and evaporated under vacuum to afford a colourless solid. Thissolid was not pure enough so it was purified again by MDAP (Formic)chromatography. Desired fractions were combined and evaporated undervacuum to afford the product as a colourless solid (38 mg).

LCMS (2 min Formic): Rt=0.59 min, [MH]⁺=310.

Example 3:rac-1-((2S,3R,4R)-4-((6-methoxypyridin-2-yl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 52.0 mg, 0.238 mmol), Pd₂(dba)₃(21.8 mg, 0.024 mmol), DavePhos (5.6 mg, 0.014 mmol), sodiumtert-butoxide (67.4 mg, 0.701 mmol), 1,4-dioxane (2 mL) and2-bromo-6-methoxypyridine (0.028 mL, 0.228 mmol). The reaction mixturewas stirred at 100° C. under nitrogen for 16 h. The reaction mixture wasallowed to cool to rt, then filtered through a celite cartridge, washingwith ethyl acetate. The filtrate was evaporated under a stream ofnitrogen and the residue dissolved in methanol (1 mL). The dissolvedmaterial was purified by MDAP (Formic). The required fractions wereevaporated under a stream of nitrogen to give the required product as abeige solid (22.8 mg, 0.070 mmol, 29.4%).

LCMS (2 min formic): Rt=0.99 min, MH⁺=326.

Example 4:rac-1-((2S,3R,4R)-4-(imidazo[1,2-a]pyridin-8-ylamino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a 0.5-2 mL microwave vial was addedrac-1-(2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 40 mg, 0.183 mmol), DavePhos (7mg, 0.018 mmol), Pd₂(dba)₃ (17 mg, 0.019 mmol), sodium tert-butoxide(26.4 mg, 0.275 mmol) and 8-bromoimidazo[1,2-a]pyridine (46 mg, 0.233mmol). The mixture was suspended in anhydrous 1,4-dioxane (1 mL). Thereaction vessel was sealed and the vial was evacuated then backfilledwith nitrogen twice. The reaction mixture was heated in a microwave at110° C. for 30 min. The reaction mixture was filtered through a layer ofcelite, washing through with EtOAc. The solvent was removed by rotaryevaporation and the residue was dissolved in anydrous 1,4-dioxane (1 mL)then transferred to a 0.5-2 mL microwave vial containing a mixture ofDavePhos (7 mg, 0.018 mmol), Pd₂(dba)₃ (17 mg, 0.019 mmol), sodiumtert-butoxide (26.4 mg, 0.275 mmol) and 8-bromoimidazo[1,2-a]pyridine(46 mg, 0.233 mmol). The reaction vessel was sealed and the solution wasbubbled with nitrogen for 10 min. The reaction mixture was heated in amicrowave at 110° C. for 30 min. The reaction mixture was filteredthrough a celite cartridge, washing through with EtOAc. The solvent wasremoved by rotary evaporation and the residue was purified by MDAP(Formic). The appropriate fractions were combined and the solvent wasremoved by rotary evaporation to give the desired product as a lightbrown solid (5 mg, 0.015 mmol, 8.16%).

LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=335.

Example 5:rac-1-((2S,3R,4R)-4-((3-methoxyphenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 35 mg, 0.160 mmol), DavePhos (7mg, 0.018 mmol), Pd₂(dba)₃ (17 mg, 0.019 mmol) and sodium tert-butoxide(25 mg, 0.260 mmol). The mixture was suspended in anhydrous 1,4-dioxane(2 mL) and to the suspension was added 1-bromo-3-methoxybenzene (24 μL,0.190 mmol). The reaction mixture was heated in a greenhouse reactor at100° C. for 2 h under an atmosphere of nitrogen. The reaction mixturewas allowed to cool, then was filtered through a celite cartridge,washing through with EtOAc. The solvent was removed by rotaryevaporation and the residue was dissolved in DMSO:MeOH (1:1) andpurified by MDAP (Formic). The appropriate fractions were combined andthe solvent was removed by rotary evaporation to give the desiredproduct as a light yellow foam (30 mg, 0.092 mmol, 57.7%).

LCMS (2 min Formic): Rt=1.08 min, [MH]⁺=325.

Example 6:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((3-morpholinophenyl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 51 mg, 0.234 mmol),4-(3-bromophenyl)morpholine (67.9 mg, 0.280 mmol), Pd₂(dba)₃ (10.70 mg,0.012 mmol), sodium tert-butoxide (33.7 mg, 0.350 mmol), BrettPhos(12.54 mg, 0.023 mmol) and 1,4-dioxane (2.5 mL). The reaction mixturewas then heated and stirred at 100° C. in a greenhouse reactor for 1 h.After cooling to rt, the reaction mixture was filtered through a pad ofcelite (rinsed with EtOAc). The filtrate was then evaporated in vacuo.The residue was purified by MDAP (Formic). The desired fractions werecombined and evaporated in vacuo to afford the desired product as abrown solid (42.5 mg).

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=380.5

Example 7:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(quinolin-5-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,formic acid salt

To a 0.5-2 mL microwave vial was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 40 mg, 0.183 mmol), DavePhos (7mg, 0.018 mmol), Pd₂(dba)₃ (17 mg, 0.019 mmol), sodium tert-butoxide (26mg, 0.271 mmol) and 5-bromoquinoline (46 mg, 0.221 mmol). The mixturewas suspended in anydrous 1,4-dioxane (1 mL). The reaction vessel wassealed and the solution was bubbled with nitrogen for 10 min. Thereaction mixture was heated in microwave at 110° C. for 30 min. Aftercooling, the reaction mixture was filtered through a celite cartridge,washing through with EtOAc. The solvent was removed by rotaryevaporation, leaving a residue which was subsequently dissolved inDMSO:MeOH (1:1), then purified by MDAP (Formic). The appropriatefractions were combined and the solvent was removed by rotaryevaporation. A 10% impurity remained and so the residue (32 mg) wasdissolved in DMSO:MeOH (1:1) then re-purified by MDAP (Formic). Theappropriate fractions were combined and the solvent was removed byrotary evaporation to give the desired product as an orange solid (23mg, 0.059 mmol, 32.1%). LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=346.

Example 8:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((3-(piperazin-1-yl)phenyl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,formic acid salt

To rac-tert-butyl4-(3-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)piperazine-1-carboxylate(for a preparation see Intermediate 7, 183.6 mg, 0.384 mmol) in methanol(4 mL) was added HCl (0.959 mL, 3.84 mmol, 4M in 1,4-dioxane). Thereaction mixture was stirred at rt for 4 h. The solution was thenevaporated in vacuo and the residue was purified by MDAP (Formic). Thedesired fractions were combined and evaporated in vacuo to afford thedesired product as a yellow solid (127.2 mg).

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=379.

Example 9:rac-1-((2S,3R,4R)-4-((4-chloro-2-methoxyphenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 39.0 mg, 0.179 mmol),1-bromo-4-chloro-2-methoxybenzene (47.5 mg, 0.214 mmol), Pd₂(dba)₃ (17.4mg, 0.019 mmol, DavePhos (7.4 mg, 0.019 mmol), sodium tert-butoxide(26.1 mg, 0.272 mmol) and 1,4-dioxane (2 mL). The reaction mixture washeated under nitrogen at 100° C. using a greenhouse reactor for 1 h 30min. The reaction mixture was allowed to cool to rt and filtered througha celite cartridge, washing with ethyl acetate. The filtrate wasevaporated in vacuo and the residue dissolved in a mixture ofmethanol:DMSO (2 mL, 1:1) and purified by MDAP (Formic). The requiredfractions were combined and evaporated in vacuo. Not all of the samplewas injected into the MDAP, hence the residues were combined, diluted inmethanol (1 mL) and purified by MDAP (Formic). The required fraction wasadded to the previous fractions and evaporated in vacuo to give therequired product as a yellow solid (30.9 mg, 0.086 mmol, 48.2% yield).This was impure so the product was dissolved in DCM (1 mL) and purifiedon a 5 g silica cartridge eluting with 20% ethyl acetate in cyclohexane.The required fractions were combined and evaporated under a stream ofnitrogen to give the required product as a yellow solid (20 mg, 0.056mmol, 31.2%).

LCMS (2 min Formic): Rt=1.26 min, [MH]⁺=359.

Example 10:rac-1-((2S,3R,4R)-1-acetyl-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2(1H)-one

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(fora preparation see Intermediate 6, 41.2 mg, 0.189 mmol),4-bromopyridin-2(1H)-one (37.4 mg, 0.215 mmol), Pd₂(dba)₃ (17.5 mg,0.019 mmol), DavePhos (7.5 mg, 0.019 mmol), sodium tert-butoxide (27.2mg, 0.283 mmol) and 1,4-dioxane (2 mL). The reaction mixture was stirredat 100° C. under nitrogen for 17 h. The reaction mixture was allowed tocool to rt and filtered through a celite cartridge, washing with ethylacetate. The filtrate was evaporated in vacuo and the residue dissolvedin methanol (1 mL). The dissolved material was purified by MDAP (HpH).The required fractions were combined and evaporated in vacuo to give ayellow solid. The product was impure and was therefore dissolved inmethanol and re-purified by MDAP (Formic). The required fraction wasevaporated under a stream of nitrogen to give the required product as ayellow gum (8.6 mg, 0.028 mmol, 14.63%). LCMS (2 min Formic): Rt=0.64min, [MH]⁺=312.

Example 11:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(Pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 47.3 mg, 0.217 mmol),2-chloropyridine (0.025 mL, 0.260 mmol), Pd₂(dba)₃ (9.92 mg, 10.83μmol), sodium tert-butoxide (31.2 mg, 0.325 mmol), DavePhos (8.53 mg,0.022 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. in a greenhouse reactor for 3 h. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo. Theresidue was purified by MDAP (Formic). The desired fractions werecombined and evaporated in vacuo to afford the desired product as acolourless solid (47.9 mg).

LCMS (2 min formic): Rt=0.54 min, [MH]⁺=296.

Example 12:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(thiophen-3-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a microwave vial was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 50 mg, 0.229 mmol),3-bromothiophene (0.021 mL, 0.229 mmol), copper powder (1.6 mg, 0.025mmol), cesium acetate (88.6 mg, 0.462 mmol) and dimethyl sulfoxide(DMSO) (0.5 mL). The reaction vessel was sealed and the mixture washeated in an oil bath at 90° C. for 68 h. The reaction mixture wasdiluted to 2 mL with methanol and purified by MDAP (Formic) (2×1 mLinjection). The required fractions were combined and evaporated under astream of nitrogen to give a brown gum (5.3 mg). The product was shownto contain some impurities by LCMS and was therefore dissolved in DCM (1mL) and loaded onto a 2 g silica cartridge and eluted with 50% ethylacetate in cyclohexane. The appropriate fraction was evaporated under astream of nitrogen to give the desired product as a yellow gum (1.8 mg,5.99 μmol, 2.62%).

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=301.0

Example 13:rac-1-((2S,3R,4R)-4-((4-chlorophenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 39.2 mg, 0.180 mmol),1-bromo-4-chlorobenzene (41.2 mg, 0.215 mmol), Pd₂(dba)₃ (17.6 mg, 0.019mmol), DavePhos (7.4 mg, 0.019 mmol), sodium tert-butoxide (26.3 mg,0.274 mmol) followed by 1,4-dioxane (2 mL). The reaction mixture washeated under nitrogen at 100° C. using a greenhouse reactor for 1.5 h.The reaction mixture was allowed to cool overnight, then was filteredthrough a celite cartridge, washing with ethyl acetate. The filtrate wasevaporated in vacuo and the residue dissolved in a mixture ofmethanol:DMSO (1 mL, 1:1) and purified by MDAP (HpH). The requiredfractions were combined and evaporated in vacuo to give the requiredproduct as a light brown solid (28.6 mg, 0.087 mmol, 48.4%).

LCMS (2 min Formic): Rt=1.19 min, [M]⁺=202 (loss of PhNH₂ ⁻).

Example 14:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((3-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 47.3 mg, 0.217 mmol),2-chloro-3-methylpyridine (0.029 mL, 0.260 mmol), Pd₂(dba)₃ (9.92 mg,10.83 μmol), sodium tert-butoxide (31.2 mg, 0.325 mmol), DavePhos (8.53mg, 0.022 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. in a greenhouse reactor for 3 h. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo. Theresidue was purified by MDAP (Formic). The desired fractions werecombined and evaporated in vacuo to afford the desired product as awhite solid (37.7 mg).

LCMS (2 min Formic): Rt=0.58 min, [MH]⁺=310.

Example 15:rac-1-((2S,3R,4R)-4-((4-methoxyphenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 35 mg, 0.160 mmol), Davephos, (7mg, 0.018 mmol), Pd₂(dba)₃ (17 mg, 0.019 mmol) and sodium tert-butoxide(25 mg, 0.260 mmol). The mixture was suspended in anhydrous 1,4-dioxane(2 mL) and to the suspension was added 4-bromoanisole (0.024 mL, 0.192mmol). The reaction mixture was heated in a greenhouse reactor at 100°C. overnight (16 h) under an atmosphere of nitrogen. The reactionmixture was filtered through a celite cartridge, washing through withEtOAc. The solvent was removed by rotary evaporation and the residue wasdissolved in a mixture DMSO:MeOH (1:1) then purified by MDAP (Formic).The appropriate fractions were combined and the solvent was removed byrotary evaporation to give the desired product as a brown solid (17 mg,0.052 mmol, 32.7%).

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=325.

Example 16:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(m-tolylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 38.8 mg, 0.178 mmol),1-bromo-3-methylbenzene (40.1 mg, 0.234 mmol), Pd₂(dba)₃ (16.6 mg, 0.018mmol), DavePhos (7.4 mg, 0.019 mmol), sodium tert-butoxide (27.2 mg,0.283 mmol) followed by 1,4-dioxane (2 mL). The reaction mixture washeated under nitrogen at 100° C. using a greenhouse reactor for 1 h 30min. The reaction mixture was allowed to cool overnight and thenfiltered through a celite cartridge, washing with ethyl acetate. Thefiltrate was evaporated in vacuo and the residue dissolved in a mixtureof methanol:DMSO (1 mL, 1:1) and purified by MDAP (HpH). The requiredfractions were combined and evaporated in vacuo to give the requiredproduct, as a light brown solid (33.5 mg, 0.109 mmol, 61.1%). LCMS (2min Formic): Rt=1.17 min, [MH]⁺=309.

Example 17:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyridin-3-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 53 mg, 0.243 mmol),3-bromo-5-methylpyridine (0.034 mL, 0.291 mmol), Pd₂(dba)₃ (11.12 mg,0.012 mmol), sodium tert-butoxide (35.0 mg, 0.364 mmol), DavePhos (9.56mg, 0.024 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. in a greenhouse reactor for 2 h. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo. Theresidue was purified by MDAP (Formic). The desired fractions werecombined and evaporated in vacuo to afford the desired product as abeige solid (49.8 mg).

LCMS (2 min formic): Rt=0.60 min, [MH]⁺=310.3

Example 18:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 40.5 mg, 0.186 mmol),2-chloropyrimidine (26.0 mg, 0.223 mmol), Pd₂(dba)₃ (8.49 mg, 9.28μmol), sodium tert-butoxide (26.7 mg, 0.278 mmol), DavePhos (7.30 mg,0.019 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. in a greenhouse reactor overnight. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo. Theresidue was purified by MDAP (Formic). The desired fractions werecombined and evaporated in vacuo to afford the desired product as abrown solid (3 mg).

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=297.

Example 19:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 41.8 mg, 0.191 mmol),2-bromo-4-methylpyridine (0.026 mL, 0.230 mmol), Pd₂(dba)₃ (8.77 mg,9.57 μmol), sodium tert-butoxide (27.6 mg, 0.287 mmol), DavePhos (7.54mg, 0.019 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. in a greenhouse reactor for 3 h. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo. Theresidue was purified by MDAP (Formic). Pure fractions were evaporated invacuo to afford the product as a colourless solid (18.4 mg). LCMS (2 minFormic): Rt=0.61 min, [MH]⁺=310.

Example 20:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(p-tolylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 38.0 mg, 0.174 mmol),1-bromo-4-methylbenzene (42.2 mg, 0.247 mmol), Pd₂(dba)₃ (16.8 mg, 0.018mmol), DavePhos (7.3 mg, 0.019 mmol), sodium tert-butoxide (26.1 mg,0.272 mmol) followed by 1,4-dioxane (2 mL). The reaction mixture washeated under nitrogen at 100° C. using a greenhouse reactor for 1 h 30min. The reaction mixture was allowed to cool overnight and thenfiltered though a celite cartridge, washing with ethyl acetate. Thefiltrate was evaporated in vacuo and the residue dissolved in a mixtureof methanol:DMSO (1 mL, 1:1) and purified by MDAP (HpH). The requiredfractions were combined and evaporated in vacuo to give the requiredproduct as a light brown solid (29.3 mg, 0.095 mmol, 54.6%). LCMS (2 minFormic): Rt=1.19 min, [MH]⁺=309.

Example 21:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 40.4 mg, 0.185 mmol),2-chloro-5-methylpyridine (0.026 mL, 0.222 mmol), Pd₂(dba)₃ (8.47 mg,9.25 μmol), sodium tert-butoxide (26.7 mg, 0.278 mmol), DavePhos (7.28mg, 0.019 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. in a greenhouse reactor for 5 h. Aftercooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo. Theresidue was purified by MDAP (Formic). The desired fractions werecombined and evaporated in vacuo to afford the product as a pink solid(37.5 mg).

LCMS (2 min Formic): Rt=0.60 min, [MH]⁺=310.

Example 22:rac-1-((2S,3R,4R)-4-((5-chloropyridin-3-yl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 39.9 mg, 0.183 mmol),3-bromo-5-chloropyridine (43.2 mg, 0.224 mmol), Pd₂(dba)₃ (16.8 mg,0.018 mmol), DavePhos (7.6 mg, 0.019 mmol), sodium tert-butoxide (26.6mg, 0.277 mmol) and 1,4-dioxane (2 mL). The reaction mixture was stirredat 100° C. under nitrogen for 17 h. The reaction mixture was allowed tocool to rt and filtered through a celite cartridge, washing with ethylacetate. The filtrate was evaporated in vacuo and the residue dissolvedin methanol (1 mL). The dissolved material was purified by MDAP (HpH).The required fractions were combined and evaporated in vacuo to give ayellow solid. The product was impure hence was dissolved in methanol andre-purified by MDAP (Formic). The required fractions were combined andevaporated under a stream of nitrogen to give the required product as abeige solid (21.3 mg, 0.065 mmol, 35.3%). LCMS (2 min Formic): Rt=0.87min, [MH]⁺=330.

Example 23:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((2-methylpyridin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 51.0 mg, 0.234 mmol), Pd₂(dba)₃(21.5 mg, 0.023 mmol), DavePhos (5.2 mg, 0.013 mmol), sodiumtert-butoxide (67.2 mg, 0.699 mmol), 1,4-dioxane (2 mL) and4-bromo-2-methylpyridine (0.033 mL, 0.280 mmol). The reaction mixturewas stirred at 100° C. under nitrogen for 16 hours. The reaction mixturewas allowed to cool to rt then filtered through a celite cartridge,washing with ethyl acetate. The filtrate was evaporated under a streamof nitrogen and the residue dissolved in methanol (1 mL). The dissolvedmaterial was purified by MDAP (Formic). The required fractions werecombined and evaporated in vacuo to give the required product, as awhite solid (61.0 mg, 0.197 mmol, 84%).

LCMS (2 min Formic): Rt=0.59 min, MH⁺=310.

Example 24:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 55 mg, 0.252 mmol),2-bromo-5-methylpyrazine (52.3 mg, 0.302 mmol), Pd₂(dba)₃ (11.54 mg,0.013 mmol), DavePhos (9.92 mg, 0.025 mmol) and 1,4-dioxane (2.5 mL).The reaction mixture was then heated and stirred at 100° C. in agreenhouse reactor for 1 h 30 min. After cooling to rt, the reactionmixture was filtered through a pad of celite (rinsed with EtOAc). Thefiltrate was then evaporated in vacuo. The residue was purified by MDAP(Formic). Desired fractions were combined and evaporated in vacuo toafford the product as a yellow solid (54.1 mg). LCMS (2 min Formic):Rt=0.79 min, [MH]⁺=311.

Examples 25a & 25b:1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(N26052-57-A2) &1-((2R,3S,4S)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 11, 167 mg) wassubmitted for chiral separation into its enantiomers (A and B) using a250×30 mm Chiralpak IC column eluting with 10% ethanol in heptane at aflow rate of 42.5 mL/min. Peak 1/Enantiomer A fractions were collectedbetween 8 and 9.5 min. Peak 2/Enantiomer B fractions were collectedbetween 10.5 and 11.5 min. Fraction solutions were combined thenevaporated to dryness to give Enantiomer A (61 mg) and Enantiomer B (66mg) as white solids.

The absolute configurations were determined by comparative vibrationalcircular dichroism (VCD), utilizing a reference VCD spectrum to make theassignments (Appl. Spectrosc. 65 (7), 699 (2011)). Conc—equimolarsolutions (0.2-M) in DCM; Cell—sealed transmission/BaF₂ windows/100 umpathlength; Spectrometer—ChirallR-2X™ FT-VCD spectrometer (BioTools,Inc.); Scan Parameters—2200-800 cm⁻¹ at 4 cm⁻¹ resolution.

Enantiomer A, Example 25b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 10% ethanol in heptane at 1 mL/min)—Rt=9.5 min, >99% ee by UV.Assigned with (2R,3S,4S) absolute configuration by VCD with a confidencelimit of >99% (based on confidence limit estimated for reference).

Enantiomer B, Example 25a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 10% ethanol in heptane at 1 mL/min)—Rt=10.3 min, >95% ee by UV.Assigned with (2S,3R,4R) absolute configuration by VCD with a confidencelimit of >99% (based on confidence limit estimated for reference).

Example 26:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone, hydrobromide (for a preparation see Intermediate 125,408 mg, 1.25 mmol), bromobenzene (0.26 mL, 2.51 mmol), DavePhos (49.6mg, 0.126 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃)(173 mg, 0.189 mmol) and sodium tert-butoxide (318 mg, 3.31 mmol) in1,4-dioxane (8.5 mL) was heated under nitrogen at 100° C. for 30 min andcooled slowly to rt and stirred for 19 h. The mixture was filteredthrough a 10 g celite cartridge, washing with ethyl acetate (3×20 mL).The combined filtrate was evaporated in vacuo and the residue was loadedin dichloromethane (˜10 mL) onto a 25 g silica cartridge and waspurified by flash column chromatography eluting with a gradient of 0-50%ethyl acetate in dichloromethane. The required fractions were combinedand evaporated in vacuo to give a brown gummy residue which wasre-dissolved in methanol (3 mL) and was purified by MDAP (Formic) (3×1mL injection). The required fractions were combined and evaporated invacuo to give the desired product (255 mg, 0.80 mmol, 64%). LCMS (2 minFormic): Rt=1.18 min, [MH]⁺=321.

Examples 27a & 27b:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone&1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3R,4R)-2-Cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 26, ˜200 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm ChiralpakAD-H column eluting with 10% ethanol in heptane at a flow rate of 20mL/min. Peak 1/Enantiomer A fractions were collected between 11 and 13min. Peak 2/Enantiomer B fractions were collected between 16 and 20 min.Fraction solutions were combined then evaporated to dryness to giveEnantiomer A (85 mg) and Enantiomer B (63 mg) as white solids. Theabsolute configurations were determined by ab initio vibrationalcircular dichroism (VCD), a form of differential vibrationalspectroscopy that combines experimental and computational VCD data todetermine absolute stereochemistry (Appl. Spectrosc. 65 (7), 699(2011)). Conc—equimolar solutions (0.2-M) in DCM; Cell—sealedtransmission/BaF₂ windows/100 um pathlength; Spectrometer—ChirallR-2X™FT-VCD spectrometer (BioTools, Inc.); Scan Parameters—2200-800 cm⁻¹ at 4cm⁻¹ resolution. Computation: Conformational Search—stochastic withMMFF94x; Model Chemistry (vibrational properties)—B3LYP/dgdzvp with PCMsolvent modelling; Spectral Synthesis—Boltzmann statistics; QuantitativeAnalysis—CompareVOA™ (BioTools, Inc.).

Enantiomer A, Example 27a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 10% ethanol in heptane at 1 mL/min)—Rt=6.0 min. >95% ee by UV.Assigned with (2S,3R,4R) absolute configuration by VCD with a confidencelimit of >99% (based on confidence limit estimated for reference).

Enantiomer B, Example 27b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 10% ethanol in heptane at 1 mL/min)—Rt=8.6 min, >99% ee by UV.Assigned with (2R,3S,4S) absolute configuration by VCD with a confidencelimit of >99% (based on confidence limit estimated for reference).

Example 28:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone, hydrobromide (for a preparation see Intermediate 125,407.5 mg, 1.253 mmol), 2-bromo-6-methylpyridine (0.286 mL, 2.51 mmol),DavePhos (49.6 mg, 0.126 mmol), tris(dibenzylideneacetone)dipalladium(0)(Pd₂(dba)₃) (177.0 mg, 0.193 mmol) and sodium tert-butoxide (313.5 mg,3.26 mmol) in 1,4-dioxane (8.5 mL) was heated under nitrogen at 100° C.for 2 h. The mixture was allowed to cool to rt and was filtered througha 10 g celite cartridge, washing with ethyl acetate (3×20 mL). Thecombined filtrate was evaporated in vacuo and the residue was loaded indichloromethane (˜10 mL) onto a 25 g silica cartridge and was purifiedby flash column chromatography eluting with a gradient of 0-50% ethylacetate in dichloromethane. The required fractions were combined andevaporated in vacuo to give a orange gummy residue which wasre-dissolved in methanol (3 mL) and was purified by MDAP (HpH) (3×1 mLinjection). The required fractions were combined and evaporated in vacuoto give the desired product as a white crunchy foam (186.0 mg, 0.554mmol, 44%). LCMS (2 min HpH): Rt=1.12 min, [MH]⁺=336.

Examples 29a & 29b:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone&1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 28, ˜170 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm ChiralcelOD-H column eluting with 10% ethanol in heptane at a flow rate of 20mL/min. Peak 1/Enantiomer A fractions were collected between 17 and 19min. Peak 2/Enantiomer B fractions were collected between 21.5 and 25min. Fraction solutions were combined then evaporated to dryness to giveEnantiomer A (78 mg) and Enantiomer B (86 mg) as white solids.

Enantiomer A, Example 29b

Analytical Chiral HPLC using a 250×4.6 mm Chiralcel OD-H column elutingwith 5% ethanol in heptane at 1 mL/min)—Rt=7.0 min. >99% ee by UV.

Enantiomer B, Example 29a

Analytical Chiral HPLC using a 250×4.6 mm Chiralcel OD-H column elutingwith 5% ethanol in heptane at 1 mL/min)—Rt=8.6 min, >95% ee by UV.

Example 30:rac-4-(((2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

Pd₂(dba)₃ (72.7 mg, 0.079 mmol), DavePhos (62.5 mg, 0.159 mmol) andsodium tert-butoxide (114 mg, 1.191 mmol) were all placed in a 2-5 mLmicrowave vial. To this was added 4-bromobenzonitrile (148.2 mg, 0.814mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 97 mg, 0.397 mmol) in1,4-dioxane (4 mL). The mixture was heated at 120° C. for 40 min in amicrowave. The mixture was filtered through a 2.5 g celite cartridge andconcentrated in vacuo to afford a dark brown oil. This was taken up inethyl acetate and purified on a silica cartridge (25 g) by flash columnchromatography, eluting with 10%-50% ethyl acetate in cyclohexane. Theappropriate fractions were combined and concentrated in vacuo in twobatches, to afford the desired product as a yellow glass (38.9 mg) and areduced purity batch of the desired product, also as a yellow glass (30mg).

LCMS (2 min Formic): Rt=1.06 min, [M−H]⁻=344.

Example 31:rac-1-((2S,3R,4R)-2-Cyclopropyl-3-methyl-4-(o-tolylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (67.7 mg, 0.074 mmol), DavePhos (58.2 mg, 0.148 mmol) andsodium tert-butoxide (107 mg, 1.109 mmol) were all placed in a 2 mLmicrowave vial. To this was added 1-bromo-2-methylbenzene (0.089 mL,0.739 mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 90.3 mg, 0.370 mmol) in1,4-dioxane (4 mL). The mixture was heated at 120° C. for 40 min in amicrowave reactor. The reaction mixture was passed through a 2.5 gcelite cartridge with ethyl acetate, and concentrated in vacuo. Themixture was taken up in ethyl acetate and purified on a silica cartridge(25 g) by flash column chromatography, eluting with 5-30% ethyl acetatein cyclohexane. The appropriate fractions were combined and concentratedin vacuo to afford an orange-brown crystalline solid (54.3 mg). LCMS (2min Formic): Rt=1.25 min, [MH]⁺=335.

Example 32:rac-1-((2S,3R,4R)-2-Cyclopropyl-4-((4-fluorophenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (42.6 mg, 0.046 mmol), DavePhos (36.6 mg, 0.093 mmol) andsodium tert-butoxide (67.0 mg, 0.697 mmol) were all placed in a 2 mLmicrowave vial. To this was added 1-bromo-4-fluorobenzene (0.051 mL,0.465 mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 56.8 mg, 0.232 mmol) in1,4-dioxane (2 mL). The mixture was heated at 120° C. for 40 min in amicrowave heater. The reaction mixture was passed through a 2.5 g celitecartridge and washed through with ethyl acetate. The solution was thenconcentrated in vacuo, taken up in ethyl acetate and purified on asilica cartridge (25 g) by flash column chromatography, eluting with0%-30% ethyl acetate in cyclohexane. The appropriate fractions werecombined and concentrated in vacuo to afford a yellow oil (40 mg). LCMS(2 min Formic): Rt=1.18 min, [M]⁺=228 (loss of NHC₆H₄F⁻).

Example 33:rac-3-(((2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

Pd₂(dba)₃ (34.9 mg, 0.038 mmol), DavePhos (30.0 mg, 0.076 mmol) andsodium tert-butoxide (55.0 mg, 0.572 mmol) were all placed in a 2 mLmicrowave vial. To this was added 3-bromobenzonitrile (69.4 mg, 0.381mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 46.6 mg, 0.191 mmol) in1,4-dioxane (2 mL). The mixture was then heated at 120° C. for 40 min ina microwave heater. The reaction mixture was passed through a 2.5 gcelite cartridge with ethyl acetate, and concentrated in vacuo. Thecrude product was taken up in dichloromethane and purified on a silicacartridge (10 g) by flash column chromatography, eluting with 5-45%ethyl acetate in cyclohexane. The appropriate fractions were collectedand evaporated in vacuo to afford a yellow solid (21.5 mg).

LCMS (2 min Formic): Rt=1.12 min, [M]⁺=228 (loss of NHC₆H₄CN⁻).

Example 34:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((3-cyclopropylphenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone,hydrobromide (for a preparation see Intermediate 125, 50.3 mg, 0.155mmol), 1-bromo-3-cyclopropylbenzene (0.041 mL, 0.309 mmol), DavePhos(6.9 mg, 0.018 mmol), Pd₂(dba)₃ (23.3 mg, 0.025 mmol) and sodiumtert-butoxide (38.1 mg, 0.396 mmol) in 1,4-dioxane (1 mL) was heatedunder nitrogen at 100° C. for 100 min. The mixture was allowed to coolto rt and was filtered through a 2.5 g celite cartridge, washing withethyl acetate (3×5 mL). The combined filtrate was evaporated under astream of nitrogen and the residue was re-dissolved in methanol/DMSO (1mL, 9:1) and was purified by MDAP (Formic). The required fraction wasevaporated under a stream of nitrogen to give the desired product as anorange/brown gum (29.7 mg, 0.082 mmol, 53.3%).

LCMS (2 min Formic): Rt=1.29 min, [MH]⁺=361.

Example 35:rac-1-((2S,3R,4R)-2-Cyclopropyl-4-((3-fluorophenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (35.7 mg, 0.039 mmol), DavePhos (30.7 mg, 0.078 mmol) andsodium tert-butoxide (56.2 mg, 0.584 mmol) were all placed in a 2 mLmicrowave vial. To this was added 1-bromo-3-fluorobenzene (0.043 mL,0.390 mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 47.6 mg, 0.195 mmol) in1,4-dioxane (2 mL). The mixture was then heated at 120° C. for 40 min ina microwave heater. The reaction mixture was filtered through a 2.5 gcelite cartridge, washed through with ethyl acetate and concentrated invacuo. The crude material was taken up in dichloromethane and purifiedon a silica cartridge (10 g) by flash column chromatography, elutingwith 5%-40% ethyl acetate in cyclohexane. The appropriate fractions werecollected and evaporated in vacuo to afford a yellow glass. The samplewas dissolved in MeOH:DMSO (1 mL, 1:1) and purified by MDAP (Formic).The solvent was evaporated in vacuo to give the required product (7.7mg).

LCMS (2 min Formic): Rt=1.20 min, [M]⁺=228 (loss of NHC₆H₄F⁻)=228.

Example 36:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (37.1 mg, 0.041 mmol), DavePhos (31.9 mg, 0.081 mmol) andsodium tert-butoxide (58.4 mg, 0.608 mmol) were all placed in a 2 mLmicrowave vial. To this was added 2-bromo-6-methoxypyridine (0.050 mL,0.405 mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 49.5 mg, 0.203 mmol) in1,4-dioxane (2 mL). The mixture was degassed with nitrogen for ˜15 min,and then heated at 120° C. for 40 min in a microwave heater. Thereaction mixture was passed through a 2.5 g celite cartridge withfurther 1,4-dioxane. The mixture was concentrated in vacuo and the crudematerial dissolved in dichloromethane. This crude material was purifiedon a silica cartridge (10 g) by flash column chromatography, elutingwith 0%-50% ethyl acetate in cyclohexane. The appropriate fractions werecombined and concentrated in vacuo to afford a yellow glass (46.9 mg).

LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=352.

Example 37:rac-2-(((2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

Pd₂(dba)₃ (35.0 mg, 0.038 mmol), DavePhos (30.1 mg, 0.076 mmol) andsodium tert-butoxide (55.1 mg, 0.573 mmol) were all placed in a 2 mLmicrowave vial. To this was added 2-bromobenzonitrile (69.6 mg, 0.382mmol), followed byrac-1-(2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 46.7 mg, 0.191 mmol) in1,4-dioxane (2 mL). The mixture was then heated at 120° C. for 40 min ina microwave heater. The vessel was resealed and heated to 120° C. for 40min in a microwave heater. The reaction mixture was filtered through a2.5 g celite cartridge with ethyl acetate, collected and concentrated invacuo. The crude product was taken up in dichloromethane and purified ona silica cartridge (10 g) by flash column chromatography, eluting with5%-45% ethyl acetate in cyclohexane. The appropriate fractions werecollected and concentrated in vacuo to afford a yellow crystalline solid(8.6 mg). The sample was dissolved in MeOH:DMSO (1 mL, 1:1) and purifiedby MDAP (Formic). The solvent was evaporated in vacuo to give therequired product (5.0 mg).

LCMS (2 min Formic): Rt=1.16 min, [M]⁺=228 (loss of NHC₆H₄CN⁻).

Example 38:rac-1-(((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (34.0 mg, 0.037 mmol), DavePhos (29.3 mg, 0.074 mmol) andsodium tert-butoxide (53.6 mg, 0.557 mmol) were all placed in a 2 mLmicrowave vial. To this was added 2-bromo-4-methylpyrimidine (73.9 mg,0.427 mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 45.4 mg, 0.186 mmol) in1,4-dioxane (2 mL). The mixture was heated at 120° C. for 40 min in amicrowave heater. A further portion of 2-bromo-4-methylpyrimidine (42.5mg) was added, the vessel resealed and the reaction heated in amicrowave heater for 20 min at 130° C. The mixture was passed through a2.5 g celite cartridge and washed through with ethyl acetate. Thecollected solution was evaporated in vacuo to afford a dark brown oil.The crude product was taken up in dichloromethane and purified on asilica cartridge (10 g) by flash column chromatography, eluting with40%-80% ethyl acetate in cyclohexane. The appropriate fractions werecollected and concentrated in vacuo to afford a yellow solid (16 mg).LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=337.

Example 39:rac-1-(((2S,3R,4R)-2-cyclopropyl-4-((3-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (75 mg, 0.082 mmol), DavePhos (64.6 mg, 0.164 mmol) and sodiumtert-butoxide (118 mg, 1.230 mmol) were all placed in a 2 mL microwavevial. To this was added 2-bromo-3-methoxypyridine (159.3 mg, 0.847mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 100.2 mg, 0.410 mmol) in1,4-dioxane (4 mL). The mixture was heated at 120° C. for 40 min in amicrowave heater. The mixture was passed through a 2.5 g celitecartridge with further 1,4-dioxane, and the concentrated in vacuo toafford a dark brown oil. This crude material was dissolved indichloromethane and purified on a silica cartridge (10 g) by flashcolumn chromatography, eluting with 10%-50% ethyl acetate incyclohexane. The desired fractions were combined and concentrated invacuo to afford the desired product as a yellow glass (126.1 mg).

LCMS (2 min Formic): Rt=0.70 min, M[H]⁺=352.

Example 40:rac-1-(((2S,3R,4R)-2-cyclopropyl-4-((6-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3R,4R)-4-Amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 45 mg, 0.184 mmol),2-bromo-6-fluoropyridine (64.8 mg, 0.368 mmol), DavePhos (29.0 mg, 0.074mmol), Pd₂(dba)₃ (33.7 mg, 0.037 mmol) and sodium tert-butoxide (53.1mg, 0.553 mmol) were combined in dry 1,4-dioxane (2 mL) in a 2 mLmicrowave vial. The reaction mixture was degassed for 15 min and thenheated at 120° C. for 40 min in the microwave. The reaction mixture wasfiltered through celite and concentrated to give a crude orange oil (178mg). This was purified on a silica cartridge (10 g) by flash columnchromatography, eluting with 0-100% ethyl acetate/cyclohexane to givethe desired product as an orange oil (36 mg).

LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=340.

Example 41:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 14, 48 mg, 0.196mmol), 2-bromo-5-fluoropyridine (69.1 mg, 0.393 mmol), DavePhos (30.9mg, 0.079 mmol), Pd₂(dba)₃ (36.0 mg, 0.039 mmol) and sodiumtert-butoxide (56.6 mg, 0.589 mmol) were combined in dry 1,4-dioxane (2mL) in a 2 mL microwave vial. The reaction mixture was degassed for 15min and then heated at 120° C. for 40 min in the microwave. Furtherportions of 2-bromo-5-fluoropyridine (69.1 mg, 0.393 mmol), DavePhos(30.9 mg, 0.079 mmol), Pd₂(dba)₃ (36.0 mg, 0.039 mmol) and sodiumtert-butoxide (56.6 mg, 0.589 mmol) were added and reaction mixtureheated for a further 40 min at 120° C. The reaction mixture was filteredthrough celite and concentrated to give a crude brown oil (314 mg). Thiswas purified on a Biotage SNAP silica cartridge (10 g) by flash columnchromatography, eluting with 0-100% ethyl acetate/cyclohexane to givethe product as an orange oil (49 mg). This was further purified bydissolving the crude sample in MeOH:DMSO (0.9 mL, 1:1) and purifying byMDAP (Formic). The fractions containing product were partitioned betweenDCM and sat. NaHCO₃ (aq solution). The organic layer was separated,dried (Na₂SO₄) and concentrated to give the product (22 mg, 0.065 mmol,33.0%) as a pale yellow solid. LCMS (2 min Formic): Rt=0.94 min,[MH]⁺=340.

Example 42:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-isopropoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (39.7 mg, 0.043 mmol), DavePhos (34.1 mg, 0.087 mmol) andsodium tert-butoxide (62.4 mg, 0.650 mmol) were all placed in a 2 mLmicrowave vial. To this was added 2-bromo-6-isopropoxypyridine (94 mg,0.433 mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 52.9 mg, 0.217 mmol) in1,4-dioxane (2 mL). The mixture was degassed with nitrogen for ˜45 min,and then heated at 120° C. for 40 min in a microwave heater. Thereaction mixture was filtered through a 2.5 g celite cartridge with1,4-dioxane, and the collected solution concentrated in vacuo. The crudematerial was dissolved in dichloromethane and purified on a silicacartridge (10 g) by flash column chromatography, eluting with 0%-50%ethyl acetate in cyclohexane. The appropriate fractions were collectedand evaporated in vacuo to afford the desired product as a pale yellowglass (60.1 mg).

LCMS (2 min Formic): Rt=1.23 min, [MH]⁺=380.

Example 43:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((4-cyclopropylphenyl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone,hydrobromide (for a preparation see Intermediate 125, 50.5 mg, 0.155mmol), 1-bromo-4-cyclopropylbenzene (0.042 mL, 0.311 mmol), DavePhos(6.2 mg, 0.016 mmol), Pd₂(dba)₃ (24.2 mg, 0.026 mmol) and sodiumtert-butoxide (38.9 mg, 0.405 mmol) in 1,4-dioxane (1 mL) was heatedunder nitrogen at 100° C. for 100 min. The mixture was allowed to coolto rt and was filtered through a 2.5 g celite cartridge, washing withethyl acetate (3×5 mL). The combined filtrate was evaporated under astream of nitrogen and the residue was re-dissolved in methanol/DMSO (1mL, 9:1) and was purified by MDAP (Formic). The required fraction wasevaporated under a stream of nitrogen to give the desired product as anorange/brown gum (21.8 mg, 0.060 mmol, 38.9%)

LCMS (2 min Formic): Rt=1.31 min, [MH]⁺=361.

Example 44:rac-4-(((2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

Pd₂(dba)₃ (27.5 mg, 0.030 mmol), DavePhos (23.65 mg, 0.060 mmol) andsodium tert-butoxide (43.3 mg, 0.451 mmol) were all placed in a 2-5 mLmicrowave vial. To this was added 4-bromo-N-methylbenzamide (64.3 mg,0.300 mmol), followed by a fine suspension ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 36.7 mg, 0.150 mmol) in1,4-dioxane (2 mL). The mixture was heated at 120° C. for 40 min in amicrowave heater. The mixture was filtered through a 2.5 g celitecartridge, washed through with ethyl acetate and concentrated in vacuoto afford a viscous orange liquid. This crude material was taken up indichloromethane and purified on a silica cartridge (10 g) by flashcolumn chromatography, eluting with 25%-100% ethyl acetate incyclohexane. The appropriate fractions were collected and evaporated invacuo to afford a yellow glass. The sample was dissolved in MeOH:DMSO (1mL, 1:1) and purified by MDAP (Formic). The solvent was evaporated invacuo to give the required product (5.8 mg). LCMS (2 min formic):Rt=0.89 min, [MH]⁺=378.

Example 45:rac-6-(((2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 41 mg, 0.168 mmol) was dissolvedin dimethyl sulfoxide (DMSO) (0.9 mL). 6-Chloronicotinonitrile (46.5 mg,0.336 mmol) and DIPEA (0.088 mL, 0.503 mmol) were added and reactionmixture was heated in a microwave vial at 200° C. for 2 h. The crudereaction mixture was dissolved in MeOH:DMSO (0.9 mL, 1:1) and purifiedby MDAP (Formic). The fractions containing product were partitionedbetween DCM and sat. NaHCO₃ (aq solution). The organic layer wasseparated, dried (Na₂SO₄) and concentrated to give the product (15 mg,0.043 mmol, 25.8%) as a yellow solid. LCMS (2 min Formic): Rt=0.98 min,[MH]⁺=347.

Example 46: rac-methyl4-(((2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate

Pd₂(dba)₃ (107 mg, 0.117 mmol), DavePhos (92 mg, 0.233 mmol) and sodiumtert-butoxide (168 mg, 1.750 mmol) were all placed in a 2-5 mL microwavevial. To this was added methyl 4-bromobenzoate (251 mg, 1.166 mmol),followed by a fine suspension ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 142.5 mg, 0.583 mmol) in1,4-dioxane (5 mL). The mixture was heated at 120° C. for 40 min in amicrowave heater. The reaction vessel was resealed and heated in amicrowave heater for a further 20 min at 140° C. The mixture wasfiltered through a 2.5 g celite cartridge, washed through with ethylacetate and concentrated in vacuo to afford a yellow crystalline solid.The crude material was taken up in dichloromethane and purified on asilica cartridge (10 g) by flash column chromatography, eluting with0%-35% ethyl acetate in cyclohexane. The appropriate fractions werecollected and evaporated in vacuo to afford a yellow crystalline solid(51.2 mg).

LCMS (2 min Formic): Rt=1.12 min, [M]⁺=228 (loss of NHC₆H₄CO₂CH₃ ⁻).

Example 47:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A stirring solution of sodium iodide (104 mg, 0.693 mmol) andrac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 36, 48.7 mg, 0.139 mmol) in acetonitrile(1.2 mL) was treated with TMSCl, (0.176 mL, 0.139 mmol, 10% v/v inacetonitrile). The mixture was heated to reflux for ˜16 h. A further 1.0eq of 10% v/v TMSCl in acetonitrile solution was added, and the reactionmixture continued to stir at reflux for a further 2 h. The mixture wasallowed to cool, and then quenched with methanol (10 mL). The mixturewas allowed to stir at rt for ˜90 min. The mixture was then concentratedin vacuo, dissolved in ethyl acetate and separated with water. Theorganic layer was washed with water (3×50 mL) and then saturated aqueoussodium chloride solution. The organic layer was dried over magnesiumsulphate and concentrated in vacuo. The crude residue was taken up indichloromethane and purified on a silica cartridge (10 g) by flashcolumn chromatography, eluting with 0-5% methanol in dichloromethane.The appropriate fractions were combined and concentrated in vacuo toafford a white crystalline solid (18.5 mg). LCMS (2 min Formic): Rt=0.76min, [MH]⁺=338.

Example 48:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Pd₂(dba)₃ (38.4 mg, 0.042 mmol), DavePhos (33.0 mg, 0.084 mmol) andsodium tert-butoxide (60.4 mg, 0.629 mmol) were all placed in a 2 mLmicrowave vial. To this was added 2-bromo-6-methylpyrazine (81 mg, 0.469mmol), followed byrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 51.2 mg, 0.210 mmol) in1,4-dioxane (2 mL). The mixture was heated at 120° C. for 40 min in amicrowave heater. The reaction mixture was passed through a 2.5 g celitecartridge and washed through with 3 CVs of ethyl acetate. The solutionwas evaporated in vacuo to afford a deep orange oil. The crude productwas taken up in dichloromethane and purified on a silica cartridge (25g) by flash column chromatography, eluting with 30%-70% ethyl acetate incyclohexane. The appropriate fractions were collected and concentratedin vacuo to afford a yellow solid (40.6 mg).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=337.

Example 49:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((3-hydroxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a stirring solution ofrac-1-((2S,3R,4R)-2-cyclopropyl-4-((3-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 39, 47 mg, 0.134 mmol) in dichloromethane(DCM) (1 mL), cooled to 0° C. under nitrogen, was added boron tribromide(0.655 mL, 0.655 mmol, 1M in DCM). The mixture was stirred at 0° C. for2 h. The mixture was allowed to warm to rt over 40 min and stirred for afurther 55 min at rt. The reaction was quenched with methanol (˜6 mL) at0° C. and concentrated in vacuo to afford a brown liquid. Theconcentrated mixture was taken up in methanol and purified on a silicacartridge (10 g) by flash column chromatography, eluting with 0-10%methanol in dichloromethane. The fractions containing product werecollected and concentrated in vacuo. The sample was dissolved inMeOH:DMSO (1 mL, 1:1) and purified by MDAP (Formic). The solvent wasevaporated in vacuo to give the required product (2.9 mg). LCMS (2 minFormic): Rt=0.65 min, [MH]⁺=338.

Example 50:rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinonitrile

rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 48 mg, 0.196 mmol) was dissolvedin dimethyl sulfoxide (DMSO) (0.9 mL). 6-chloropicolinonitrile (54.4 mg,0.393 mmol) and DIPEA (0.103 mL, 0.589 mmol) were added and reaction washeated in a microwave vial at 200° C. for 2 h. The crude reactionmixture was dissolved in MeOH:DMSO (0.9 mL, 1:1) and purified by MDAP(Formic). The fractions containing product were partitioned between DCMand sat. NaHCO₃ (aq solution). The organic layer was separated, dried(Na₂SO₄) and concentrated to give the product (5.5 mg, 0.016 mmol,8.08%) as a pale yellow oil. LCMS (2 min Formic): Rt=1.04 min,[MH]⁺=347.

Example 51:rac-1-((2S,3R,4R)-2-cyclobutyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 0.5-2 mL microwave vessel was charged with a magnetic stirrer bar,sodium tert-butoxide (45 mg, 0.468 mmol), Pd₂(dba)₃ (14 mg, 0.015 mmol),DavePhos (12 mg, 0.030 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclobutyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 18, 80 mg, 0.31 mmol), bromobenzene(0.035 mL, 0.332 mmol) and anhydrous 1,4-dioxane (1.0 mL). The vesselwas sealed and nitrogen was bubbled through the reaction mixture for 5min. The reaction was heated in a using a microwave reactor at 120° C.for 30 min. The reaction mixture was filtered through celite and washedwith EtOAc (8 mL). The filtrate was evaporated under vacuum and theresidue purified by MDAP (Formic). The appropriate fractions werecombined and the solvent evaporated in vacuo to give the product as anoff-white solid (32 mg, 0.096 mmol, 31%). LCMS (2 min Formic): Rt=1.24min, [MH]⁺=335.

Example 52:rac-1-((2S,3R,4R)-2-isopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 0.5-2 mL microwave vessel was charged with a magnetic stirrer bar,sodium tert-butoxide (70 mg, 0.728 mmol), Pd₂(dba)₃ (23 mg, 0.025 mmol),DavePhos (19 mg, 0.048 mmol),rac-1-((2S,3R,4R)-4-amino-2-isopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 21, 120 mg, 0.487 mmol),bromobenzene (0.051 mL, 0.487 mmol) and anhydrous 1,4-dioxane (4 mL).The vessel was sealed and nitrogen was bubbled through the reactionmixture for 5 min. The reaction was heated in a microwave reactor at110° C. for 30 min. The reaction mixture was filtered through celite andwashed with EtOAc (10 mL). The filtrate was evaporated under vacuum andthe residue purified by MDAP (Formic). The appropriate fractions werecombined and the solvent was removed by rotary evaporation to give theproduct as an off-white solid (80 mg, 0.248 mmol, 51%).

LCMS (2 min Formic): Rt=1.21 min, [MH]⁺=323.

Example 53:rac-1-((2S,3R,4R)-3-methyl-4-(phenylamino)-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 0.5-2 mL microwave vessel was charged with a magnetic stirrer bar,sodium tert-butoxide (45 mg, 0.468 mmol), Pd₂(dba)₃ (14 mg, 0.015 mmol),DavePhos (12 mg, 0.030 mmol),rac-1-((2S,3R,4R)-4-amino-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(90 mg, 0.314 mmol), bromobenzene (for a preparation see Intermediate24, 0.035 mL, 0.332 mmol) and anhydrous 1,4-dioxane (1.25 mL). Thevessel was sealed and nitrogen was bubbled through the reaction mixturefor 5 min. The reaction was heated in a microwave reactor at 120° C. for30 min. The reaction mixture was filtered through celite and washed withEtOAc (8 mL). The filtrate was evaporated under vacuum and the residuepurified by MDAP (Formic). The desired product was sent to the waste andso the waste was evaporated under vacuum. The residue was purified byMDAP (Formic). The appropriate fractions were combined and the solventevaporated in vacuo to give the product as a light brown foam (53 mg,0.146 mmol, 47%). LCMS (2 min Formic): Rt=1.18 min, [MH]⁺=363.

Example 54:rac-1-((2R,3R,4R)-2-(methoxymethyl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2R,3R,4R)-2-(hydroxymethyl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 29, 36 mg, 0.116 mmol) in anhydrousTHE (1 mL) was added sodium hydride (60% in mineral oil) (6 mg, 0.150mmol) and the mixture stirred under nitrogen at 0° C. for 15 min. Methyliodide (7.5 μl, 0.120 mmol) was added and the mixture stirred at rt for5 h. The reaction mixture was quenched by the addition of water (3 mL)and the mixture extracted with EtOAc (3 mL). The organic extract waswashed with water (3 mL) and dried through a hydrophobic frit. Thesolvent was removed under vacuum and the residue was purified by MDAP(Formic). The appropriate fractions were combined and the solventremoved by rotary evaporation to give the product as a colourless gum(11 mg, 0.034 mmol, 29%).

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=325.

Example 55:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-onehydrobromide (for a preparation see Intermediate 31, 80 mg, 0.236 mmol),bromobenzene (0.05 mL, 0.471 mmol), DavePhos (10 mg, 0.025 mmol),Pd₂(dba)₃ (33 mg, 0.036 mmol) and sodium tert-butoxide (60 mg, 0.62mmol) in 1,4-dioxane (2 mL) was heated under nitrogen at 100° C. for 90min. The mixture was allowed to cool to rt and was filtered through a2.5 g celite cartridge, washing with ethyl acetate (3×5 mL). Thecombined filtrate was evaporated under a stream of nitrogen and theresidue was re-dissolved in 9:1 methanol/DMSO (1 mL) and was purified byMDAP (Formic) (1 mL injection). As all of the sample was not injected, afurther purification using the remaining crude solution was undertaken(1 mL injection; formic). The required fractions were combined andevaporated in vacuo to give the desired product as a pale yellow crunchyfoam (65 mg, 0.196 mmol, 83%). LCMS (2 min Formic): Rt=1.26 min,[MH]⁺=335.

Example 56:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one

rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (for a preparation see Intermediate 31, 58 mg,0.224 mmol), 2-bromo-6-methylpyridine (77 mg, 0.45 mmol), DavePhos (35mg, 0.09 mmol), Pd₂(dba)₃ (41 mg, 0.045 mmol) and sodium tert-butoxide(65 mg, 0.673 mmol) were combined in dry 1,4-dioxane (2 mL) in a 2 mLmicrowave vial. The reaction mixture was degassed for 15 min and thenheated at 120° C. for 40 min in the microwave. The reaction mixture wasfiltered through celite and concentrated to give 180 mg of crude brownoil. This was purified by chromatography on silica gel (10 g) elutingwith 0-50% ethyl acetate/cyclohexane over 120 mL to give the product (60mg, 0.172 mmol, 76%) as a yellow oil.

LCMS (2 min HpH): Rt=0.77 min, [MH]⁺=350.

Example 57:rac-1-((2S,3S,4R)-2-cyclopropyl-3-methyl-4-(methyl(phenyl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-(2S,3S,4R)-2-cyclopropyl-N,3-dimethyl-N-phenyl-1,2,3,4-tetrahydroquinolin-4-amine(for a preparation see Intermediate 34, 70 mg, 0.239 mmol) and pyridine(0.077 mL, 0.96 mmol) in dichloromethane (DCM) (1.04 mL) stirred undernitrogen was added acetyl chloride (0.026 mL, 0.36 mmol) drop-wise. Thereaction mixture was stirred at rt for 30 min. The reaction mixture waspartitioned between dichloromethane (10 mL) and saturated sodiumbicarbonate solution (10 mL). The aqueous layer was extracted with DCM(10 mL) and the combined organics dried through a phase separator andevaporated to dryness. The crude product was added to a 25 g silica gelcolumn and was eluted with 10-30% EtOAc/cyclohexane. Collected fractionswere evaporated to afford the product (50 mg, 0.147 mmol, 61%). A secondbatch of less pure material (90%) was also collected (10 mg). LCMS (2min Formic): Rt=1.36 min, [MH]⁺=335.

Example 58:rac-1-((2S,3R,4R)-6-methoxy-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-6-methoxy-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 37, 521 mg, 2.10 mmol), bromobenzene(0.287 mL, 2.73 mmol), DavePhos (82 mg, 0.209 mmol), Pd₂(dba)₃ (188.7mg, 0.206 mmol) and sodium tert-butoxide (334 mg, 3.48 mmol) in1,4-dioxane (20 mL) was heated under nitrogen at 100° C. for 1.5 h.After leaving to stand at rt for 17 h, further bromobenzene (0.144 mL,1.367 mmol) was added and the stirred mixture was heated for a further 3hours at 100° C. After cooling furthertris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃) (90 mg, 0.099mmol) was added and heating at 100° C. was continued for a further 3.5h. The reaction mixture was filtered through a 10 g celite cartridge,which was subsequently eluted with ethyl acetate (3×20 mL). The combinedfiltrate was evaporated in vacuo and the residue was loaded indichloromethane (˜10 mL) onto a 50 g silica cartridge and was purifiedby flash column chromatography eluting with a gradient of 0-50% ethylacetate in dichloromethane. The required fractions were combined andevaporated in vacuo to give the desired product as an orange crunchyfoam (268 mg, 0.825 mmol, 39%).

LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=325.

Example 59:rac-1-((2S,3R,4R)-6-hydroxy-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a stirred solution ofrac-1-((2S,3R,4R)-6-methoxy-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 58, 265 mg, 0.816 mmol) indichloromethane (DCM) (10 mL) cooled to 0° C. (ice bath) under nitrogenwas added boron tribromide (1M solution in dichloromethane) (4.0 mL,4.00 mmol). After 90 min the cooling bath was removed and the mixtureallowed to warm to rt. After stirring at rt for 1 h 2M hydrochloric acid(5 mL) was added carefully to the mixture and stirring was continued for5 min. The phases were separated and water (5 mL) was added to theaqueous phase which was extracted with ethyl acetate (2×15 mL). Thecombined organic phases (dichloromethane and ethyl acetate) were dried(MgSO₄), filtered and evaporated to give a residue which was loaded in10:1 dichloromethane/methanol (˜10 mL) onto a 25 g silica cartridge andwas purified by flash column chromatography eluting with a gradient of0-80% ethyl acetate in dichloromethane. The required fractions werecombined and evaporated in vacuo to give the desired product as a yellowcrystalline solid (122 mg, 0.393 mmol, 48%).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=311.

Example 60:rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yltrifluoromethanesulfonate

To a stirred solution ofrac-1-((2S,3R,4R)-6-hydroxy-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 59, 119 mg, 0.382 mmol) in drytetrahydrofuran (THF) (3 mL) cooled to 0° C. (ice bath) and stirredunder nitrogen was added sodium tert-butoxide (43 mg, 0.45 mmol). After5 minutes1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(152 mg, 0.424 mmol) was added and stirring continued. After 3 h further1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(41 mg, 0.115 mmol) was added to the mixture and stirring continued fora further 15 min. After a total of 4 h stirring at 0° C. the mixture wasallowed to warm to rt and was partitioned between saturated aqueoussodium bicarbonate solution (5 mL) and ethyl acetate (5 mL). The phaseswere separated and the aqueous phase extracted with further ethylacetate (3×5 mL). The combined organic phases were filtered through acartridge fitted with a hydrophobic frit and evaporated under a streamof nitrogen. The residue was loaded in dichloromethane (˜2 mL) onto a 10g silica cartridge and was purified by flash column chromatographyeluting with a gradient of 0-60% ethyl acetate in dichloromethane. Therequired fractions were combined and evaporated in vacuo to give thedesired product as a yellow solid (133 mg, 0.301 mmol, 79%).

LCMS (2 min Formic): Rt=1.25 min, [MH]⁺=443.

Example 61:rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel,rac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 50 mg, 0.20 mmol), DavePhos (12mg, 0.03 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol) and sodium tert-butoxide(65 mg, 0.676 mmol) were added in 1,4-dioxane (5 mL).2-Bromo-6-methylpyridine (0.034 mL, 0.30 mmol) was added and thereaction left to stir at 100° C. under nitrogen for 3 h. The mixture wasfiltered through celite and the celite washed with ethyl acetate (2×10mL). The combined filtrates were washed with water (2×25 mL) and thelayers separated. The organic layer was passed through a hydrophobicfrit and concentrated in vacuo to give an orange solid. This waspurified by chromatography on silica gel (10 g) eluting with 0-75% ethylacetate/cyclohexane. The fractions containing only product were combinedand concentrated in vacuo to give the product (22 mg, 0.064 mmol, 32%)as a yellow solid. LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=342.

Example 62:rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

To a reaction vesselrac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 171 mg, 0.68 mmol), DavePhos (54mg, 0.137 mmol), sodium tert-butoxide (250 mg, 2.60 mmol) and Pd₂(dba)₃(100 mg, 0.109 mmol) were added in 1,4-dioxane (5 mL).4-Bromobenzonitrile (187 mg, 1.03 mmol) was added and the vessel heatedto 100° C. for 3 h whilst stirring. The reaction mixture was filteredthrough celite and the celite washed with ethyl acetate (2×15 mL). Thecombined filtrates were washed with water (2×30 mL) and separated. Theorganic layer was passed through a hydrophobic frit and concentrated invacuo to give 450 mg of a brown gum. This was purified by chromatographyon silica gel (25 g) eluting with 0-35% ethyl acetate/cyclohexane. Noproduct was isolated so the column was run again with 0-10% DCM/methanoland the fractions containing pure product were combined and concentratedin vacuo to give 64 mg of product as a yellow solid. The fractionscontaining impure product were combined and concentrated in vacuo togive 161 mg of impure brown gum. The impure product was purified bychromatography on silica gel (10 g) eluting with cyclohexane/ethylacetate (0-50%). The fractions containing product were combined andconcentrated in vacuo to give a yellow solid. This was combined with theearlier material to give the product (74 mg) as a yellow solid.

LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=352.

Example 63:rac-1-((2S,3R,4R)-2-cyclopropyl-7-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of 2-bromo-6-methylpyridine (0.13 mL, 1.115 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-7-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 43, 146 mg, 0.56 mmol), DavePhos (22mg, 0.056 mmol), Pd₂(dba)₃ (74 mg, 0.081 mmol), sodium tert-butoxide (90mg, 0.93 mmol)) in 1,4-dioxane (10 mL) was heated to 100° C. for 2 hunder nitrogen. The reaction mixture was filtered through a celitecartridge, washed with ethyl acetate and the solvent was evaporatedunder a stream of nitrogen to give a dark red gum residue. The residuewas re-dissolved in methanol (3 mL) and purified by MDAP (HpH). Thethird injection was made up of the remaining sample of the first twoMDAP runs, the appropriate fractions were combined and evaporated undera stream of nitrogen to give the product (45 mg). This sample wasre-dissolved in methanol (1 mL) and again purified MDAP (HpH). Theappropriate fractions were combined and evaporated under a stream ofnitrogen to give the final product (38 mg).

LCMS (2 min Formic): Rt=1.17 min, [MH]⁺=354.

Example 64:rac-1-((2S,3R,4R)-2-cyclopropyl-7-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanoneformic acid salt

A mixture of 2-bromo-6-methylpyridine (0.17 mL, 1.46 mmol), DavePhos (29mg, 0.073 mmol), Pd₂(dba)₃ (101 mg, 0.11 mmol), and sodium tert-butoxide(111 mg, 1.16 mmol) was added torac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-7-methoxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 46, 200 mg, 0.73 mmol) in1,4-dioxane (10 mL) and heated to 100° C. for 2 h under nitrogen. Thereaction mixture was filtered through a celite cartridge, washed withethyl acetate and the solvent was evaporated under a stream of nitrogento give a dark red gum residue. The residue was re-dissolved in methanol(3 mL) and purified by MDAP (Formic). The appropriate fractions werecollected and evaporated under a stream of nitrogen to give the desiredproduct (146 mg). LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=366.

Example 65:rac-1-((2S,3R,4R)-2-cyclopropyl-7-hydroxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a stirred solution ofrac-1-((2S,3R,4R)-2-cyclopropyl-7-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,formic acid salt (for a preparation see Example 64, 100 mg, 0.243 mmol)in dichloromethane (DCM) (3 mL) cooled to 0° C. under nitrogen was addedboron tribromide (0.115 mL, 1.215 mmol) and the reaction was stirred for90 min. The reaction mixture was removed from the ice bath and graduallywarmed to 20° C. where stirring continued for 60 min. Hydrochloric acid(2M, 1 mL) was carefully added and stirring continued for 5 min. Thephases were separated and water (1 mL) was added to the aqueous phasewhich was extracted with ethyl acetate (2×3 mL). The organic phases werecombined and passed through a hydrophobic frit and solvent evaporatedunder a stream of nitrogen. The yellow residue was re-dissolved inmethanol (1 mL) and purified by MDAP (HpH) and appropriate fractionswere combined and collected. The solvent was evaporated under a streamof nitrogen. Due to a high percent of impurity, purification wasrepeated twice by MDAP (Formic) repeating the procedure above to givethe product as a colourless glass (3 mg, 8.54 μmol, 4%). LCMS (2 minFormic): Rt=0.59 min, [MH]⁺=352.

Example 66:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile

The 2-bromo-6-methylpyridine (0.043 mL, 0.371 mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for preparation see Intermediate 49, 50 mg, 0.186 mmol), DavePhos (7mg, 0.02 mmol), Pd₂(dba)₃ (26 mg, 0.028 mmol), sodium tert-butoxide (54mg, 0.557 mmol) and 1,4-dioxane (8 mL) were placed in a round bottomedflask and allowed to stir at 100° C. for 16 h. The reaction was treatedwith further DavePhos (7 mg, 0.019 mmol), sodium tert-butoxide (54 mg,0.557 mmol) and Pd₂dba₃ (26 mg, 0.028 mmol), the reaction was allowed tostir at 100° C. for 3 h. The reaction was allowed to cool to rt and waspartitioned between water and EtOAc, the organic phase was washed withbrine, dried using a hydrophobic frit and concentrated to a gum. Thisgum was purified using a column chromatography (10 g silica) elutingwith 0-50% EtOAc:cyclohexane. The fractions relating to product weresummed and concentrated to give the product (16 mg) as an orange solid.

LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=361.

Example 67:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(methylsulfonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3R,4R)-4-Amino-2-cyclopropyl-3-methyl-6-(methylsulfonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 51, 40 mg, 0.124 mmol), DavePhos(5.9 mg, 0.015 mmol), 2-bromo-6-methylpyridine (0.017 mL, 0.149 mmol),Pd₂(dba)₃ (6.8 mg, 7.44 μmol) and sodium tert-butoxide (26 mg, 0.273mmol) in 1,4-dioxane (2 mL) was stirred under nitrogen at 90° C. for 16h. The reaction mixture was filtered through celite, rinsed with ethylacetate then concentrated in vacuo to recover starting material. Allreactants were added again and the reaction mixture was left to stirunder nitrogen at 90° C. for 4 h. The reaction mixture was allowed tocool to rt then was filtered through celite and washed with ethylacetate. The solvent was evaporated to give 150 mg crude as an orangegum. The sample was dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified byMDAP (Formic). The appropriate fractions were combined and concentratedin vacuo. The product was dissolved in methanol then applied to a 5 gNH₂ cartridge which had been pre-equilibrated with methanol (5 mL). Thecolumn was flushed with methanol (5 mL) and the fraction wasconcentrated under a stream of nitrogen. The product was dissolved in1:1 MeOH:DMSO (1 mL) and purified by MDAP (HpH). The appropriatefractions were combined and concentrated in vacuo to give the product (8mg, 0.019 mmol, 16%). LCMS (2 min Formic): Rt=0.60 min, [MH]⁺=414.

Example 68:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(isopropylsulfonyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of sodium tert-butoxide (50 mg, 0.520 mmol), Pd₂(dba)₃ (12 mg,0.013 mmol), DavePhos (11 mg, 0.028 mmol) andrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(isopropylsulfonyl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 53, 83 mg, 0.237 mmol) in anhydrous1,4-dioxane (2 mL) was treated with 2-bromo-6-methylpyridine (0.032 mL,0.284 mmol) and stirred at 100° C. under nitrogen for 16 h. The reactionmixture was allowed to cool to rt and filtered through cotton wool. Thefiltrate was applied to a MeOH pre-conditioned 2 g SCX-2 cartridge whichwas then washed with MeOH (10 mL) followed by 2M ammonia/MeOH (10 mL).The basic wash was evaporated under vacuum and the residue purified byMDAP (HpH). The appropriate fractions were combined and the solventremoved by rotary evaporation to give the product as an off-white powder(18 mg, 0.041 mmol, 17%). LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=442.

Example 69:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 55, 24.3 mg, 0.051 mmol) in methanol(0.5 mL) was added HCl in dioxane (0.127 mL, 0.508 mmol). The reactionmixture was stirred at rt for 3 h. The reaction mixture was thenevaporated in vacuo and was purified by MDAP (Formic) to give theproduct (13 mg, 67%) as a black solid.

LCMS (2 min Formic): Rt=0.67 min, [MH]⁺=379.

Example 70:rac-1-((2S,3R,4R)-2,3-dimethyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Under nitrogen atmosphere, to a solution of bromobenzene (0.063 mL,0.593 mmol) in 1,4-dioxane (8 mL) were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 56, 150 mg, 0.494 mmol), DavePhos(19.46 mg, 0.049 mmol), Pd₂(dba)₃ (22.64 mg, 0.025 mmol) and sodiumtert-butoxide (71.3 mg, 0.742 mmol). The reaction was irradiated in amicrowave at 110° C. for 30 minutes. The reaction was treated withfurther tris Pd₂(dba)₃ (22.64 mg, 0.025 mmol), DavePhos (19.46 mg, 0.049mmol), sodium tert-butoxide (71.3 mg, 0.742 mmol) and bromobenzene(0.063 mL, 0.593 mmol) and the reaction irradiated at 110° C. for 30minutes. This was repeated one more time, however at the end of the 30min, the vial was found broken in the microwave reactor. A maximum ofthe reaction mixture was retrieved using methanol, the resultingsolution was evaporated in vacuo and the residue was transferred into a2-5 mL microwave vial. Pd₂(dba)₃ (22.64 mg, 0.025 mmol), DavePhos (19.46mg, 0.049 mmol), sodium tert-butoxide (71.3 mg, 0.742 mmol) andbromobenzene (0.063 mL, 0.593 mmol) were added and the reactionirradiated in a microwave at 110° C. for 30 min. This was repeated twomore times as the starting material was still present. At the end of thelast reaction the vial was found broken again in the reactor. Likebefore, the reaction mixture was retrieved with methanol and theresulting solution was evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with 0-60% of ethyl acetatein cyclohexane to give crude product which was further purified using aMDAP (Formic) to give the product (29 mg, 15%) as a orange solid. LCMS(2 min Formic): Rt=1.03 min, [MH]⁺=380.

Example 71a & 71b:1-((2S,3R,4R)-2,3-dimethyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(71a) &1-((2R,3S,4S)-2,3-dimethyl-6-morpholino-4-(phenylamino)-3.4-dihydroquinolin-1(2H)-yl)ethanone(71b)

1-((2S,3R,4R)-2,3-dimethyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 70, 29 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm ChiralpakAD-H column eluting with 10% ethanol in heptane at a flow rate of 45mL/min. Peaks 1 and 2 were collected separately and then evaporated todryness to give Enantiomer A (12 mg) and Enantiomer B (12 mg) as whitesolids.

Enantiomer A, Example 71b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 10% ethanol in heptane at 1 mL/min)—Rt=9.5 min. >99% ee by UV.

Enantiomer B, Example 71a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 10% ethanol in heptane at 1 mL/min)—Rt=13.0 min, >99% ee by UV.

Example 72:1-((rac-2S,3R,4R)-2,3-dimethyl-6-(3-methylpiperazin-1-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,formate salt

To a solution of tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 58, 7.4 mg, 0.015 mmol) in methanol(0.5 mL) was added HCl (4M in 1,4-dioxane) (150 μL, 0.600 mmol). Thereaction mixture was stirred at rt for 23 h. The solvent was evaporatedin vacuo and the residue purified MDAP (Formic) to the product (4.1 mg,8.81 μmol, 58.6%). This was a racemic mixture of diastereoisomers. LCMS(2 min Formic): Rt=0.69 min, [MH]⁺=393.

Example 73:rac-1-((2S,3R,4R)-2,3-dimethyl-6-morpholino-4-(pyridin-3-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Under a nitrogen atmosphere, to a solution of 3-bromopyridine (0.016 mL,0.164 mmol) in 1,4-Dioxane (3 mL) were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 56, 41.4 mg, 0.136 mmol), DavePhos(5.37 mg, 0.014 mmol), Pd₂(dba)₃ (6.25 mg, 6.82 μmol) and sodiumtert-butoxide (19.67 mg, 0.205 mmol). The reaction was irradiated in amicrowave at 110° C. for 30 min. The reaction was treated with further3-bromopyridine (0.016 mL, 0.164 mmol), Pd₂(dba)₃ (6.25 mg, 6.82 μmol),DavePhos (5.37 mg, 0.014 mmol) and sodium tert-butoxide (19.67 mg, 0.205mmol) and irradiated in a microwave at 110° C. for 30 min. This processwas repeated one more time. After cooling to rt, the reaction mixturewas filtered through a pad of celite (rinsed with EtOAc). The filtratewas then evaporated in vacuo and purified by column chromatography onsilica gel eluting with 0-10% of methanol in DCM to give crude productwhich was further purified by MDAP (Formic) to give the product (10 mg,20%) as a yellow solid. LCMS (2 min Formic): Rt=0.56 min, [MH]⁺=381

Example 74:rac-1-((2S,3R,4R)-6-(4-aminopiperidin-1-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,hydrochloride

To rac-tert-butyl(1-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-4-yl)carbamate(for a preparation see Intermediate 61, 12.5 mg, 0.025 mmol) in methanol(0.2 mL) was added 4M HCl in 1,4-dioxane (0.063 mL, 0.254 mmol). Thereaction mixture was stirred at rt for 4 h. The solution was thenevaporated in vacuo and the residue was purified by chromatography onsilica gel eluting with 0-20% of methanol in DCM to give the product (7mg, 62%) as a yellow solid. LCMS (2 min Formic): Rt=0.71 min, [MH]⁺=393.

Example 75:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(For a preparation see Intermediate 56, 53.2 mg, 0.175 mmol),2-chloro-6-methylpyridine (0.021 mL, 0.269 mmol), Pd₂(dba)₃ (9.95 mg,10.87 μmol), sodium tert-butoxide (31.4 mg, 0.327 mmol), DavePhos (8.54mg, 0.022 mmol) and 1,4-Dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. for 4 h. After cooling to rt, the reactionmixture was filtered through a pad of celite (rinsed with EtOAc). Thefiltrate was then evaporated in vacuo and purified by MDAP (Formic) togive the product (29 mg, 42%) as a yellow solid.

LCMS (2 min Formic): Rt=0.59 min, [MH]⁺=395.

Example 76:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-6-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To rac-tert-butyl4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)amino)piperidine-1-carboxylate(for a preparation see Intermediate 64, 10.8 mg, 0.022 mmol) in methanol(0.2 mL) was added 4M HCl in 1,4-dioxane (0.055 mL, 0.219 mmol). Thereaction mixture was stirred at rt for 6 h. The solution was thenevaporated in vacuo and the residue purified by chromatography on silicagel eluting with 0-20% (2M ammonia in methanol) in DCM to give theproduct: (1.7 mg, 20%) as a yellow solid.

LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=300 (loss of NHPh⁻).

Example 77:1-((rac-2S,3R,4R)-2,3-dimethyl-6-(2-methylmorpholino)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of1-((rac-2S,3R,4R)-4-amino-2,3-dimethyl-6-(2-methylmorpholino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 65, 5.9 mg, 0.019 mmol) in1,4-dioxane (0.5 mL) was added bromobenzene (5 μL, 0.047 mmol),Pd₂(dba)₃ (1.1 mg, 1.201 μmol), DavePhos (0.9 mg, 2.287 μmol) and sodiumtert-butoxide (3.2 mg, 0.033 mmol). The reaction mixture was heated at100° C. for 18 h. The reaction mixture was allowed to cool to rt thenloaded onto a 2.5 g celite cartridge, eluted with ethyl acetate thenconcentrated. To the residue was added 1,4-dioxane (0.5 mL), sodiumtert-butoxide (3.4 mg, 0.035 mmol), DavePhos (2 mg, 5.08 μmol),Pd₂(dba)₃ (2 mg, 2.184 μmol) and bromobenzene (10 μL, 0.094 mmol). Thereaction mixture was heated at 100° C. for a further 21 h. The reactionmixture was allowed to cool to rt then loaded onto a 2.5 g celitecartridge, eluted with ethyl acetate the filtrate was concentrated andpurified by MDAP (Formic) to give the product (6.4 mg, 0.016 mmol, 87%).This was a racemic mixture of diastereoisomers.

LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=394.

Example 78:1-((rac-2S,3R,4R)-6-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,2 Hydrochloride

To a solution of tert-butyl5-((rac-2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate(for a preparation see Intermediate 67, 4.7 mg, 9.31 μmol) in methanol(0.2 mL) was added HCl (4M in 1,4-dioxane) (0.093 mL, 0.373 mmol). Thereaction mixture was stirred at rt under nitrogen for 70.5 h. Thesolvent was evaporated under a stream of nitrogen to give the product(4.5 mg, 8.48 μmol, 91%). This was a racemic mixture ofdiastereoisomers. LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=405.

Example 79:rac-1-((2S,3R,4R)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2S,3R,4R)-4-amino-6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 68, 5.6 mg, 0.017 mmol) in1,4-dioxane (0.5 mL) was added bromobenzene (5 μL, 0.047 mmol),Pd₂(dba)₃ (2.1 mg, 2.293 μmol), DavePhos (2.1 mg, 5.34 μmol) and sodiumtert-butoxide (3.6 mg, 0.037 mmol). The reaction mixture was stirred at100° C. for 18 h. The reaction mixture was allowed to cool to rt thenloaded onto a 2.5 g celite cartridge, eluted with ethyl acetate thenevaporated under a stream of nitrogen. To the residue was added1,4-dioxane (0.5 mL), bromobenzene (10 μL, 0.094 mmol), Pd₂(dba)₃ (2.1mg, 2.293 μmol), DavePhos (2.1 mg, 5.34 μmol) and sodium tert-butoxide(3.4 mg, 0.035 mmol). The reaction mixture was stirred at 100° C. for afurther 21 h. The reaction mixture was allowed to cool to rt then loadedonto a 2.5 g celite cartridge, eluted with ethyl acetate then evaporatedunder a stream of nitrogen. To the residue was added 1,4-dioxane (0.5mL), bromobenzene (10 μL, 0.094 mmol), Pd₂(dba)₃ (1.9 mg, 2.075 μmol),DavePhos (2.2 mg, 5.59 μmol) and sodium tert-butoxide (3.7 mg, 0.039mmol). The reaction mixture was stirred for a further 6 h. The reactionmixture was allowed to cool to rt then loaded onto a 2.5 g celitecartridge, eluted with ethyl acetate then evaporated under a stream ofnitrogen. The residue was purified by MDAP (Formic) to give the product(2.3 mg, 5.67 μmol, 33.4%). LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=406.

Example 80:1-((rac-2S,3R,4R)-2,3-dimethyl-6-(3-methylpyrrolidin-1-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube was added1-((rac-2S,3R,4R)-4-amino-2,3-dimethyl-6-(3-methylpyrrolidin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 69, 25.7 mg, 0.085 mmol),bromobenzene (11 μL, 0.103 mmol), Pd₂(dba)₃ (4.6 mg, 5.02 μmol),DavePhos (3.8 mg, 9.66 μmol), sodium tert-butoxide (11.1 mg, 0.116 mmol)and 1,4-dioxane (1 mL). The reaction mixture was stirred at 100° C.under nitrogen for 16 h. The reaction mixture was allowed to cool to rtthen loaded onto a 2.5 g celite cartridge, eluted with ethyl acetatethen evaporated under a stream of nitrogen. To the residue was added1,4-dioxane (1 mL), DavePhos (3.8 mg, 9.66 μmol), Pd₂(dba)₃ (4.1 mg,4.48 μmol), sodium tert-butoxide (11.8 mg, 0.123 mmol) and bromobenzene(11 μL, 0.103 mmol). The reaction mixture was stirred at 100° C. undernitrogen for a further 4 h. The reaction mixture was allowed to cool tort then loaded onto a 2.5 g celite cartridge, eluted with ethyl acetatethen evaporated under a stream of nitrogen. The residue was purified byMDAP (Formic) to give 1 the product (18.9 mg, 0.050 mmol, 58.7%) as ayellow/orange gum. This was a racemic mixture of diastereoisomers. LCMS(2 min Formic): Rt=1.32 min, [MH]⁺=378.

Example 81:1-((rac-2S,3R,4R)-2,3-dimethyl-6-(2-methylpyrrolidin-1-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a greenhouse test tube was added1-((rac-2S,3R,4R)-4-amino-2,3-dimethyl-6-(2-methylpyrrolidin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 70, 7.5 mg, 0.058 mmol),bromobenzene (7.5 μL, 0.070 mmol), Pd₂(dba)₃ (3.1 mg, 3.39 μmol),DavePhos (2.7 mg, 6.86 μmol), sodium tert-butoxide (8.1 mg, 0.084 mmol)and 1,4-dioxane (1 mL). The reaction mixture was stirred at 100° C.under nitrogen for 16 h. The reaction mixture was allowed to cool to rtthen loaded onto a 2.5 g celite cartridge, eluted with ethyl acetatethen evaporated under a stream of nitrogen. To the residue was added1,4-dioxane (1 mL), DavePhos (2.7 mg, 6.86 μmol), Pd₂(dba)₃ (3.1 mg,3.39 μmol), sodium tert-butoxide (8.4 mg, 0.087 mmol) and bromobenzene(7.5 μL, 0.070 mmol). The reaction mixture was stirred at 100° C. undernitrogen for a further 4 h. The reaction mixture was allowed to cool tort then loaded onto a 2.5 g celite cartridge, eluted with ethyl acetatethen evaporated under a stream of nitrogen. The residue was purified byMDAP (Formic) to give the product (11.0 mg, 0.029 mmol, 50.2%) as ayellow gum. This was a racemic mixture of diastereoisomers. LCMS (2 minFormic): Rt=1.23 min, [MH]⁺=378.

Example 82:rac-1-((2S,3R,4R)-6-(-3,8-diazabicyclo[3.2.1]octan-3-yl)-2,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,2 Hydrochloride

To a solution of rac-(1R,5S)-tert-butyl3-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(for a preparation see Intermediate 72, 3.3 mg, 6.54 μmol) in methanol(0.2 mL) was added HCl (4M in 1,4-dioxane) (0.065 mL, 0.262 mmol). Thereaction mixture was stirred at rt under nitrogen for 70.5 h. Thesolvent was evaporated under a stream of nitrogen to give the product(2.6 mg, 4.90 μmol, 74.9%).

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=405.

Example 83:rac-6-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

To a solution ofrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 56, 16.2 mg, 0.053 mmol) inN-methyl-2-pyrrolidone (NMP) (0.5 ml) were added 6-chloronicotinonitrile(14.80 mg, 0.107 mmol) and DIPEA (0.028 ml, 0.160 mmol). Using amicrowave reactor the solution was stirred and irradiated withmicrowaves so as to maintain a temperature of 200° C. for 2 h. Thereaction mixture was then concentrated in vacuo and the residue waspurified by MDAP (Formic) chromatography. Desired fractions werecombined and evaporated in vacuo to afford the product as a beige solid(1.7 mg).

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=406.

Example 84:rac-1-((2S,3R,4R)-2-ethyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a 10 mL round bottomed flask was added Pd₂(dba)₃ (6.5 mg, 7.10 μmol),DavePhos (5.6 mg, 0.014 mmol), sodium tert-butoxide (20.2 mg, 0.210mmol),rac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 73, 46.2 mg, 0.146 mmol) and1,4-dioxane (2 mL). Bromobenzene (18 μL, 0.169 mmol) was then added andthe reaction mixture heated at 100° C. under nitrogen for 45 min.Further bromobenzene (18 μL, 0.169 mmol) was added and stirringcontinued for a further 16 h at 100° C. The reaction mixture was allowedto cool, then further Pd₂(dba)₃ (6.9 mg, 7.54 μmol) and DavePhos (5.9mg, 0.015 mmol) were added and stirring continued for a further 3 h.Further bromobenzene (19 μl, 0.179 mmol) was added and stirringcontinued for a further 19 h. The reaction mixture was allowed to coolto rt. The reaction mixture was filtered through a celite cartridge andwashed with ethyl acetate. The residue was by MDAP (Formic) to give theproduct (13.2 mg, 0.034 mmol, 23.05%) as a yellow solid.

LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=394.

Example 85:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,formic acid salt

The 2-chloro-6-methylpyridine (61.0 mg, 0.478 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 78 mg, 0.239 mmol), DavePhos(9.40 mg, 0.024 mmol), Pd₂(dba)₃ (32.8 mg, 0.036 mmol), sodiumtert-butoxide (68.9 mg, 0.717 mmol) and 1,4-dioxane (10 mL) were placedin a round bottomed flask and allowed to stir at 100° C. for 18 h. Thereaction was partitioned between water and EtOAc, the aqueous layer wasextracted with further EtOAc and the combined organics washed withbrine, dried using a hydrophobic frit and concentrated to a yellow gum.This gum was purified by chromatography on silica gel eluting with 0-50%EtOAc:cyclohexane to give the product (76 mg, 68%) as a yellow solidLCMS (2 min Formic): Rt=0.75 min, [MH]⁺=418

Example 86:1-((rac-2S,3R,4R)-2-cyclopropyl-3-methyl-6-(3-methylpiperazin-1-yl)-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 80, 34 mg, 0.064 mmol) and TFA (0.2mL, 2.60 mmol) were added in dichloromethane (DCM) (5 mL). The reactionwas left to stir at rt for 17.5 h. The reaction mixture was concentratedand purified by SPE on aminopropyl (NH₂) 2 g eluting with methanol togive crude product which was purified by chromatography on silica geleluting with 0-4% 2M ammonia in methanol/dichloromethane to give theproduct (10 mg, 36%). This was a racemic mixture of diastereoisomers.LCMS (2 min Formic): Rt=0.57 min, [MH]⁺=434.

Example 87:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 82, 104 mg, 0.201 mmol) was taken upin dichloromethane (DCM) (10 mL) and treated with TFA (0.078 mL, 1.006mmol) the resulting solution was allowed to stir at rt for 16 h. Thereaction was concentrated and eluted through a SCX SPE (2 g) elute MeOHand 2M NH₃/MeOH, the ammonia fraction was concentrated and dried to givea brown gum a portion of which was further purified using a MDAP(Formic) to give the product (3 mg, 4%) as a white solid.

LCMS (2 min Formic): Rt=0.52 min, [MH]⁺=417.

Example 88:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 87, 50 mg, 0.120 mmol) was taken up inethanol (10 mL) treated with 10% Pd/C (128 mg, 0.120 mmol) and allowedto stir at rt under a atmosphere of hydrogen for 4 h. The catalyst wasremoved by filtering through celite washing with EtOH. The filtrate wasconcentrated and purified using a MDAP (HpH) to give the product (9 mg,18%) as a white solid. LCMS (2 min Formic): Rt=0.99 min, [MH]⁺=419.

Example 89:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel DavePhos (16 mg, 0.041 mmol), Pd₂(dba)₃ (51 mg,0.056 mmol), sodium tert-butoxide (93 mg, 0.968 mmol),2-bromo-6-methylpyridine (0.104 mL, 0.692 mmol) andrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 83, 114 mg, 0.346 mmol) were addedin 1,4-dioxane (5 mL) and the reaction was left to stir at 100° C. Thereaction mixture was filtered through celite and washed with ethylacetate. The combined filtrates were concentrated in vacuo and purifiedby chromatography on silica gel eluting with 20-80% ethylacetate:dichloromethane to give the product (28 mg, 0.067 mmol, 19.24%)as a beige solid. LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=421.

Example 90:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

In a test tuberac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 83, 90 mg, 0.273 mmol), bromobenzene(0.035 mL, 0.328 mmol), sodium tert-butoxide (52.5 mg, 0.546 mmol),Pd₂(dba)₃ (12.51 mg, 0.014 mmol) and DavePhos (10.75 mg, 0.027 mmol)were dissolved in 1,4-dioxane (3 mL). The tube was placed in aGreenhouse Reactor and heated at 100° C. for 2 h. The reaction mixturewas filtered through a plug of celite and washed through with extra1,4-dioxane. The filtrate was evaporated to leave the crude which waspurified by column chromatography using silica gel eluting with 0-50%ethyl acetate:cyclohexane to give the product (60 mg, 54%) as anoff-white solid.

LCMS (2 min Formic): Rt=1.11 min, [MH]⁺=406.

Example 91a & 91b:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(91a) &1-((2R,3S,4S)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(91b)

rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Example 90, 60 mg) was submittedfor chiral separation into its enantiomers (A and B) using a 250×20 mmChiralpak IC column eluting with 10% ethanol in 90% heptane (plus 0.2%isopropylamine) at a flow rate of 20 mL/min. Peak 1/Enantiomer Afractions were collected between 15 and 17 min. Peak 2/Enantiomer Bfractions were collected between 18.5 and 21 min. Fraction solutionswere combined then evaporated to dryness to give Enantiomer A (24 mg)and Enantiomer B (23 mg) as white solids.

Enantiomer A, Example 91b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 10% ethanol in heptanes (plus 0.2% isopropylamine) at 1mL/min—Rt=15.5 min. >99% ee by UV.

Enantiomer B, Example 91a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 10% ethanol in heptane (plus 0.2% isopropylamine) at 1mL/min—Rt=18.2 min, >99% ee by UV.

Example 92:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The 2-bromopyridine (78 mg, 0.496 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 81 mg, 0.248 mmol), DavePhos(9.77 mg, 0.025 mmol), Pd₂(dba)₃ (34.1 mg, 0.037 mmol), sodiumtert-butoxide (71.5 mg, 0.744 mmol) and 1,4-dioxane (10 mL) were placedin a round bottomed flask and allowed to stir at 100° C. for 3 days. Thereaction was partitioned between water and EtOAc, the organic layer waswashed with brine, dried using a hydrophobic frit and concentrated to agum. This gum was purified by chromatography on silica gel eluting with0-50% EtOAc:Cyclohexane to give the product (32 mg, 32%) as an orangesolid. LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=404.

Example 93:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,Formic acid salt (for a preparation see example 85, 56 mg, 0.134 mmol)was taken up in ethanol (10 mL) and the reaction was hydrogenated usingthe H-cube (settings: 25° C., 1 bar, 1 mL/min flow rate) and 10% Pd/CCatCart 30 as the catalyst. The sample was allowed to cycle through theH-cube for 90 min. The reaction was concentrated, dried and purifiedusing MDAP (Formic) to give the product (12 mg, 21%) as a white solid.

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=420.

Example 94:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone,hydrochloride

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 85, 43 mg, 0.085 mmol) was dissolvedin methanol (1 mL) and treated with 4M hydrochloric acid (0.021 mL,0.085 mmol) in 1,4-dioxane. The reaction was stirred for 1 h and thenthe solvent and excess HCl were removed under reduced pressure to leavethe crude product which was purified by MDAP (Formic) to give productbut this was contaminated with the N-formyl by-product. This wasdissolved in MeOH (0.5 mL) and treated with base K₂CO₃ (100 mg). Thesolution was stirred overnight and then this was dissolved in DCM (0.5mL) and treated with 1M HCl in Et₂O (0.1 mL). The resulting solid wastrituated and the solvent was carefully pipetted off. The resultingsolid was dried to give the product (25 mg, 66%) as a tan solid. LCMS (2min Formic): Rt=0.75 min, [MH]⁺=405.

Example 95:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-((tetrahydro-2H-pyran-4-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The 2-bromo-6-methylpyridine (0.052 mL, 0.453 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone((for a preparation see Intermediate 88, 78 mg, 0.226 mmol), DavePhos(8.91 mg, 0.023 mmol), Pd₂(dba)₃ (31.1 mg, 0.034 mmol), sodiumtert-butoxide (65.3 mg, 0.679 mmol) and 1,4-dioxane (10 mL) were placedin a round bottomed flask and allowed to stir at 100° C. for 16 h. Thereaction was partitioned between water and EtOAc, the aqueous layer wasextracted with further EtOAc, the combined organics were washed withbrine, dried using a hydrophobic frit and concentrated to a gum. Thisgum was purified by chromatography on silica gel eluting with 5-60%EtOAc:Cyclohexane to give the product (51 mg, 52%) as a orange solid.LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=436.

Example 96:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel DavePhos (15 mg, 0.038 mmol), Pd₂(dba)₃ (53 mg,0.058 mmol), sodium tert-butoxide (100 mg, 1.041 mmol), 2-bromopyridine(0.091 mL, 0.692 mmol) andrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 83, 114 mg, 0.346 mmol) were addedin 1,4-dioxane (5 mL) and the reaction was left to stir at 100° C. Thereaction mixture was filtered through celite and washed with ethylacetate. The combined filtrates were concentrated in vacuo to a crudebrown gum. This was purified by chromatography silica gel eluting with20-80% ethyl acetate in dichloromethane to give the product (12 mg, 8%)as a beige solid. LCMS (2 min Formic): Rt=0.65 min, [MH]⁺=407.

Example 97:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of bromobenzene (0.020 mL, 0.190 mmol), DavePhos (4.4 mg,0.011 mmol), Pd₂(dba)₃ (12.4 mg, 0.014 mmol) and sodium tert-butoxide(18.4 mg, 0.191 mmol) was added torac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 90, 39.1 mg, 0.116 mmol) in1,4-dioxane (2 mL) and heated to 100° C. for 15.5 h under nitrogen. Thereaction mixture was filtered using a celite cartridge, washed withethyl acetate and the solvent was evaporated. The residue was purifiedby MDAP (Formic) to give the product (17 mg, 48%) as a pale brown gum.

LCMS (2 min Formic): Rt=1.13 min, [MH]⁺=415.

Example 98:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 92, 39.8 mg, 0.123 mmol),bromobenzene (0.021 ml, 0.199 mmol), Pd₂(dba)₃ (12.8 mg, 0.014 mmol),DavePhos (4.5 mg, 0.011 mmol), and sodium tert-butoxide (20 mg, 0.208mmol) in 1,4-dioxane (2 mL) and heated to 100° C. for 15.5 h undernitrogen. The reaction mixture was filtered using a celite cartridge,washed with ethyl acetate and then solvent was evaporated and purifiedby MDAP (Formic) to give the product (8 mg, 15%) as a pale brown gum.

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=308.

Example 99:rac-4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoicacid

A mixture ofrac-4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoicacid (for a preparation see Intermediate 94, 28.4 mg, 0.078 mmol),bromobenzene (0.016 mL, 0.156 mmol), DavePhos (3.6 mg, 9.15 μmol),Pd₂(dba)₃ (11.7 mg, 0.013 mmol) and sodium tert-butoxide (13.2 mg, 0.137mmol) in 1,4-dioxane (1 mL) was heated under nitrogen at 100° C. 1.75 h,further sodium tert-butoxide (9.6 mg, 0.100 mmol) was added and heatingcontinued for a further 1.5 h. After leaving to cool and stand at rt for15.75 h, further bromobenzene (0.032 mL, 0.304 mmol) was added andheating at 100° C. continued for a further 4.5 h. The mixture wasallowed to cool to rt and was filtered through a 2.5 g celite cartridge,washing with ethyl acetate and methanol. The combined filtrates wereevaporated under a stream of nitrogen. The residue was redissolved in1,4-dioxane (1 mL) and had fresh reagents added as follows; bromobenzene(0.025 mL, 0.234 mmol), DavePhos (4.0 mg, 10.16 μmol), Pd₂(dba)₃ (11.2mg, 0.012 mmol), sodium tert-butoxide (20.2 mg, 0.210 mmol) and1,4-dioxane (1 mL). The mixture was again heated at 100° C. undernitrogen for 2.75 h before further DavePhos (16.7 mg, 0.042 mmol) andPd₂(dba)₃ (55.9 mg, 0.061 mmol) were added and heating at 100° C.continued for a further 45 min. After cooling, the mixture waspartitioned between saturated aqueous sodium bicarbonate solution (4 mL)and dichloromethane (5 mL). The phases were separated and the aqueousphase further extracted with dichloromethane (2×5 mL). The combinedorganics were concentrated and purified by MDAP (Formic) to give theproduct (4.4 mg, 9.99 μmol, 12.82%) as a cream solid.

LCMS (2 min Formic): Rt=1.12 min, [M−H]⁻=439.

Example 100:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

Under nitrogen atmosphere, to a solution of bromobenzene (0.058 mL,0.540 mmol) in 1,4-dioxane (3 mL) were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone (for a preparation see Intermediate 97, 79 mg, 0.360mmol), BrettPhos (19.34 mg, 0.036 mmol), Pd₂(dba)₃ (16.50 mg, 0.018mmol) and sodium tert-butoxide (51.9 mg, 0.540 mmol). Using a microwavereactor the solution was stirred and irradiated with microwaves so as tomaintain a temperature of 110° C. for 30 min. The solution wastransferred into another 2-5 mL microwave vial using a syringe.Bromobenzene (0.058 mL, 0.540 mmol), Pd₂(dba)₃ (16.50 mg, 0.018 mmol),BrettPhos (19.34 mg, 0.036 mmol) and sodium tert-butoxide (51.9 mg,0.540 mmol) were added, the reaction mixture was stirred and irradiatedwith microwaves so as to maintain a temperature of 110° C. for 30 min.The reaction mixture was filtered through a pad of celite (rinsed withEtOAc). The filtrate was then evaporated in vacuo. The residue wasloaded onto a 25 g SNAP cartridge and purified by column chromatographyusing a gradient 0-10% of MeOH in DCM. Desired fractions were combinedand evaporated in vacuo to afford a yellow solid. This residue waspurified by MDAP (Formic) chromatography. Desired fractions werecombined and evaporated in vacuo to afford a yellow solid. This solidwas dissolved in DCM and loaded onto a 10 g SNAP cartridge and purifiedby column chromatography using a gradient 0-100% of ethyl acetate incyclohexane. Desired fractions were combined and evaporated in vacuo toafford a white solid. This solid was purified by MDAP (Formic)chromatography. Desired fractions were combined and evaporated in vacuoto afford the product as a beige solid (7 mg). LCMS (2 min Formic):Rt=0.80 min, [MH]⁺=296.

Example 101:rac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one

A mixture ofrac-1-((2S,3R,4R)-2-cyclopropyl-6-methoxy-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 101, 458 mg, 1.303 mmol) and sodiumiodide (1172 mg, 7.82 mmol) was diluted with acetonitrile (8 mL) andTMSCl (0.999 mL, 7.82 mmol) added. The mixture was stirred undernitrogen at 55° C. for 3 h. The reaction solution was allowed to cool tort and evaporated under vacuum. The residue was partitioned betweenwater (10 mL) and EtOAc (10 mL). The organic layer was separated andextracted with EtOAc (2×10 mL). The organic extracts were combined,dried through a hydrophobic frit and the solvent removed under vacuum.The residue was loaded in CHCl₃ (8 mL) and purified on a 100 g silicacartridge using a gradient of 0-10% MeOH in DCM over 12 CVs. Theappropriate fractions were combined and the solvent removed by rotaryevaporation to give the product (312 mg, 0.925 mmol, 71%) as a darkbrown gum which was used as an intermediate for synthesis of furtherexamples. 30 mg of the intermediate was purified by MDAP (Formic). Theappropriate fractions were combined and the solvent evaporated under astream of nitrogen to give the product as a light brown solid (13 mg,0.039 mmol). LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=338.

Example 102a & 102b:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(102a) &1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(102b)

A mixture ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 300mg, 0.639 mmol), triethylamine (0.534 mL, 3.83 mmol). Pd(dppf)Cl₂ (354mg, 0.432 mmol) and formic acid (0.123 mL, 3.20 mmol) in DMF (10 mL) wasstirred under nitrogen at 60° C. for 1 h. The solution was applieddirectly to a 20 g Flash SCX SPE column which had been pre-equilibriatedwith MeOH (30 mL). The column was flushed with MeOH (30 mL) then withMeOH/NH₃ (2M, 30 mL). All fractions were combined and concentrated invacuo and the SCX method was repeated. The MeOH/NH₃ fractions werecombined and evaporated. The samples were dissolved in 1:1 MeOH:DMSO(3×1 mL) and purified by MDAP (HpH). The appropriate fractions wereconcentrated in vacuo to leave the racemic product (92 mg). LCMS (2 minFormic): Rt=0.95 min, [MH]⁺=322.rac-1-((2S,3R,4R)-2-Cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone,92 mg) was submitted for chiral separation into its enantiomers (A andB) using a 250×30 mm Chiralpak IA column eluting with 25% ethanol inheptane at a flow rate of 30 mL/min. Peak 1/Enantiomer A fractions werecollected between 5.5 and 6.5 min. Peak 2/Enantiomer B fractions werecollected between 10 and 14 min. Fraction solutions were combined thenevaporated to dryness to give Enantiomer A (40 mg) and Enantiomer B (40mg) as white solids.

Enantiomer A, Example 102a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 25% ethanol in heptane at 1 mL/min—Rt=4.8 min. >99% ee by UV.

Enantiomer B, Example 102b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 25% ethanol in heptane at 1 mL/min—Rt=7.2 min, >99% ee by UV.

Example 103:rac-4-((6S,7R,8R)-5-Acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-N-methylbenzamide

A mixture ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 75mg, 0.160 mmol),N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (50.1mg, 0.192 mmol), PdCl₂(dppf) (17.53 mg, 0.024 mmol) and potassiumcarbonate (66.2 mg, 0.479 mmol) in 1,4-dioxane (1.4 mL) and water (0.350mL) was stirred under nitrogen at 100° C. for 1 h. The reaction mixturewas concentrated in vacuo and diluted with DCM, then washed with water(3×10 mL) and dried with a hydrophobic frit. The solution was applied toa 5 g Flash SCX SPE column which had been pre-equilibriated with MeOH(20 mL). The column was flushed with MeOH (20 mL) then with MeOH/NH₃(2M, 20 mL). The MeOH/NH₃ fraction was collected and the solvent wasevaporated to give a crude brown gum (72 mg). The sample was dissolvedin 1:1 MeOH:DMSO (1 mL) and purified by MDAP (HpH). The appropriatefractions were combined and concentrated in vacuo to give the product(15 mg, 0.033 mmol, 21%) as a yellow gum. LCMS (2 min Formic): Rt=1.07min, [MH]⁺=455.

Example 104:rac-5-((6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-N-methylpicolinamide

A mixture ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 75mg, 0.160 mmol), potassium carbonate (66.2 mg, 0.479 mmol), PdCl₂(dppf)(17.53 mg, 0.024 mmol) andN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(50.2 mg, 0.192 mmol) in 1,4-dioxane (1.400 mL) and water (0.35 mL) wasstirred under nitrogen at 100° C. for 4 h. The reaction mixture wasconcentrated in vacuo then dissolved in DCM. This solution was washedwith water (3×10 mL), dried through a hydrophobic frit and concentratedin vacuo to give a dark red gum. The samples were dissolved in 1:1MeOH:DMSO (2×1 mL) and purified by MDAP (HpH). The solvent wasevaporated in vacuo. The sample was dissolved in MeOH (2 mL) and wasapplied to a 2 g Flash SCX SPE column which had been pre-equilibriatedwith MeOH (10 mL). The column was flushed with MeOH (10 mL) then withMeOH/NH₃ (2 M, 10 mL). The MeOH/NH₃ fraction was collected and thesolvent was evaporated to give the product (14 mg, 0.031 mmol, 19%) as ayellow gum. LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=456.

Example 105:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(6-methoxypyridin-3-yl)-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 75mg, 0.160 mmol),2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (45.1mg, 0.192 mmol), PdCl₂(dppf) (17.53 mg, 0.024 mmol) and potassiumcarbonate (66.2 mg, 0.479 mmol) in 1,4-dioxane (1.4 mL) and water (0.35mL) was stirred under nitrogen at 100° C. for 1 h. The reaction mixturewas allowed to cool then concentrated in vacuo. The sample was dilutedwith DCM (7 mL), washed with water (3×10 mL) and dried through ahydrophobic frit. The solution was applied to a 5 g Flash SCX SPE columnwhich had been pre-equilibriated with MeOH. The column was flushed withMeOH then with MeOH/NH₃ (2 M). The MeOH/NH₃ fraction was collected andthe solvent was evaporated to give a brown gum. The sample was dissolvedin 1:1 MeOH:DMSO (1 mL) and purified by MDAP (HpH). The solvent wasevaporated in vacuo to give the product (25.1 mg, 0.059 mmol, 37%) as aclear gum. LCMS (2 min Formic): Rt=1.27 min, [MH]⁺=429.

Example 106:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A solution ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (for a preparation see Intermediate 102, 55mg, 0.117 mmol),1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (31mg, 0.140 mmol), PdCl₂(dppf) (13 mg, 0.018 mmol) and potassium carbonate(49 mg, 0.355 mmol) in water (0.250 mL) and 1,4-dioxane (1 mL) washeated for 1 h at 100° C. The mixture was concentrated in vacuo andseparated between DCM (10 mL) and water (10 mL). The aqueous phase wasextracted with DCM (2×10 mL) and the combined organic phases were washedwith water (2×10 mL), dried through a hydrophobic frit and concentratedin vacuo. The sample was dissolved in DMSO:MeOH (1:1, 1 ml) and purifiedby 2×MDAP (Formic). The appropriate fractions were combined andconcentrated in vacuo to give the product (5.6 mg, 12%).

LCMS (2 min Formic): Rt=1.14 min, [MH]⁺=416

Example 107:1-((rac-2S,3R,4R)-2-cyclopropyl-3-methyl-6-(3-methylpiperazin-1-yl)-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

To a solution of tert-butyl4-((rac-6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 103, 11 mg, 0.021 mmol) in1,4-dioxane (0.1 mL) was added 4 M HCl in 1,4-dioxane (0.212 mL, 0.847mmol). The reaction mixture was stirred at rt in a closed vessel for 1h. The reaction mixture was concentrated under a stream of nitrogen thendissolved in MeOH (1 mL). The solution was applied directly to a 2 gFlash SCX SPE column which had been pre-equilibriated with MeOH. Thecolumn was flushed with MeOH (6 mL) then with MeOH/NH₃ (2M, 6 mL). TheMeOH/NH₃ fraction was concentrated under a stream of nitrogen to givethe product (7.1 mg, 0.017 mmol, 80%) as a yellow gum. This was aracemic mixture of diastereoisomers.

LCMS (2 min Formic): Rt=0.78 min, [MH]⁺=420.

Example 108:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-6-(piperazin-1-yl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A solution of rac-tert-butyl4-((6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)piperazine-1-carboxylate(for a preparation see Intermediate 104, 12 mg, 0.024 mmol) and 4M HClin 1,4-dioxane (250 μl, 1.000 mmol) in 1,4-dioxane (0.1 mL) was stirredin a closed vessel at rt for 1 h. The sample was concentrated under astream of nitrogen then dissolved in 1:1 MeOH:DMSO (1 mL) and purifiedby MDAP (HpH). The solvent was evaporated in vacuo to give the product(5.4 mg, 0.013 mmol, 56%) as a clear gum.

LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=406.

Example 109:rac-1-((2S,3R,4R)-6-(4-aminopiperidin-1-yl)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A mixture of rac-tert-butyl(1-((6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-(phenylamino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)piperidin-4-yl)carbamate(for a preparation see Intermediate 105, 8 mg, 0.015 mmol) and 4M HCl in1,4-dioxane (0.2 mL, 0.800 mmol) in 1,4-dioxane (0.1 mL) was stirred atrt in a closed vessel for 1 h. The reaction mixture was concentratedunder a stream of nitrogen then dissolved in MeOH (1 mL). The solutionwas applied directly to a 2 g Flash SCX SPE column which had beenpre-equilibriated with MeOH. The column was flushed with MeOH (6 mL)then with MeOH/NH₃ (2 M, 6 mL). The MeOH/NH₃ fraction was concentratedunder a stream of nitrogen to give the product (2.1 mg, 5.01 μmol, 33%).

LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=420.

Example 110:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-morpholino-4-(phenylamino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 109, 63.4 mg, 0.192 mmol), Pd₂(dba)₃(8.79 mg, 9.59 μmol), sodium tert-butoxide (27.7 mg, 0.288 mmol),DavePhos (7.55 mg, 0.019 mmol) and bromobenzene (0.021 mL, 0.195 mmol)in 1,4-dioxane (2.5 mL) was heated to 100° C. for 20 h. The reactionmixture was filtered through celite, washed with ethyl acetate thenconcentrated in vacuo. The sample was dissolved in DMSO:MeOH (1:1, 2×1mL) and purified by 2×MDAP (HpH). The appropriate fractions werecombined and concentrated in vacuo. The sample was purified on a ZorbaxSB phenyl column (150 mm×21.2 mm, 7.0 μm) at 20 mL/min flow rate.Gradient elution was carried out at ambient temperature, with the mobilephases as (A) water containing 0.1% (v/v) TFA and (B) acetonitrile. TheUV detection was a summed signal from wavelength of 210 nm to 400 nm.The appropriate fractions were dried under a stream of nitrogen andcombined to give the product (19.3 mg, 25%).

LCMS (2 min Formic): Rt=1.15 min, [MH]⁺=407.

Example 111:rac-1-((2S,3R,4R)-2-cyclopropyl-6-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-methoxy-3-methyl-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 100, 500 mg, 1.816 mmol),2-bromo-6-methylpyridine (0.248 ml, 2.179 mmol), DavePhos (71.5 mg,0.182 mmol), Pd₂(dba)₃ (83 mg, 0.091 mmol) and sodium tert-butoxide (262mg, 2.72 mmol) in 1,4-dioxane (6 mL) was heated at 100° C. undernitrogen for 1 h. The reaction mixture was allowed to cool to rt,filtered through celite and rinsed with ethyl acetate. The solvent wasthen evaporated in vacuo. The crude material was dissolved in DCM,loaded onto a 100 g silica cartridge and purified over a gradient of0-75% cyclohexane/(1% NEt₃/ethyl acetate) over 10 CVs. The appropriatefractions were concentrated in vacuo to give the product (445 mg, 1.214mmol, 66.9%).

LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=367.

Example 112:rac-1-((2S,3R,4R)-2-cyclopropyl-6-hydroxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-1-((2S,3R,4R)-2-cyclopropyl-6-methoxy-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(for a preparation see Example 111, 455 mg, 1.242 mmol), sodium iodide(1117 mg, 7.45 mmol) and TMSCl (0.952 mL, 7.45 mmol) in acetonitrile (10mL) was stirred under nitrogen at 45° C. for 3 h. The reaction mixturewas allowed to cool to rt and was concentrated in vacuo. The sample wasthen dissolved in MeOH and applied directly to a 20 g Flash SCX SPEcolumn which had been pre-equilibriated with MeOH (20 mL). The columnwas flushed with MeOH (20 mL) then with MeOH/NH₃ (2M, 20 mL). TheMeOH/NH₃ fraction was concentrated under a stream of nitrogen to givethe product (400 mg, 1.135 mmol, 91%).

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=353.

Example 113:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone

A mixture ofrac-(6S,7R,8R)-5-acetyl-6-cyclopropyl-7-methyl-8-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yltrifluoromethanesulfonate (188.5 mg, 0.389 mmol), Pd(dppf)Cl₂ (216 mg,0.264 mmol), formic acid (0.075 ml, 1.945 mmol) and triethylamine (0.325ml, 2.334 mmol) in DMF (7 mL) was stirred at 60° C. under nitrogen for 3h. The reaction mixture was allowed to cool to rt and applied directlyto a 20 g Flash SCX SPE column which had been pre-equilibriated withMeOH (20 mL). The column was flushed with MeOH then with MeOH/NH₃ (2M,20 mL). The MeOH/NH₃ (20 mL) fractions were combined and concentratedunder vacuum. The sample was dissolved in 1:1 MeOH:DMSO (2×1 mL) andpurified by MDAP (HpH). The appropriate fractions were combined andconcentrated in vacuo to give the product (86.3 mg, 0.257 mmol, 65.9%).

LCMS (2 min Formic): Rt=0.57 min, [MH]⁺=337.

Examples 114a and 114b:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(114a) &1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(114b)

rac-1-((2S,3R,4R)-2-Cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethanone(for a preparation see Example 113, 86 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm Chiralpak IAcolumn eluting with 10% ethanol in heptanes (plus 0.2% isopropylamine)at a flow rate of 35 mL/min. Peak 1/Enantiomer A fractions werecollected between 7.5 and 8.5 min. Peak 2/Enantiomer B fractions werecollected between 11.5 and 14 min. Fraction solutions were combined thenevaporated to dryness to give Enantiomer A (35 mg) and Enantiomer B (43mg) as white solids.

Enantiomer A, Example 114a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IA column elutingwith 10% ethanol in heptane (plus 0.2% isopropanol) at 1 mL/min—Rt7.0=min. >99% ee by UV.

Enantiomer B, Example 114b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IA column elutingwith 10% ethanol in heptanes (plus 0.2% isopropanol) at 1 mL/min—Rt=9.5min, >99% ee by UV.

Example 115:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(phenylamino)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanoneformate

Under a nitrogen atmosphere, to a solution of bromobenzene (0.047 mL,0.445 mmol) in 1,4-dioxane (3 mL) were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 114, 108.5 mg, 0.297 mmol),BrettPhos (15.94 mg, 0.030 mmol), Pd₂(dba)₃ (13.59 mg, 0.015 mmol) andsodium tert-butoxide (42.8 mg, 0.445 mmol). Using a microwave reactorthe solution was stirred and irradiated with microwaves so as tomaintain a temperature of 110° C. for 30 min. The solution wastransferred into another 2-5 mL microwave vial using a syringe,bromobenzene (0.047 mL, 0.445 mmol), Pd₂(dba)₃ (13.59 mg, 0.015 mmol),BrettPhos (15.94 mg, 0.030 mmol) and sodium tert-butoxide (42.8 mg,0.445 mmol) were added, the reaction mixture was stirred and irradiatedwith microwaves so as to maintain a temperature of 110° C. for 30 min.The reaction mixture was filtered through a pad of celite (rinsed withEtOAc). The filtrate was then evaporated in vacuo. The residue wasloaded onto a 25 g SNAP cartridge and purified by column chromatographyusing a gradient 0-100% of ethyl acetate in cyclohexane over 10 CVs,followed by 100% of ethyl acetate over 10 CVs. Desired fractions werecombined and evaporated in vacuo to afford a yellow residue. Thisresidue was purified by MDAP (Formic). Desired fractions were combinedand evaporated in vacuo to afford the product as a brown solid (4.2 mg).LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=296

Example 116:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 118, 46.3 mg, 0.189 mmol),bromobenzene (0.030 mL, 0.226 mmol), Pd₂(dba)₃ (8.64 mg, 9.44 μmol),sodium tert-butoxide (27.2 mg, 0.283 mmol), DavePhos (7.43 mg, 0.019mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was then heated andstirred at 100° C. for 4 h. After cooling to rt, the reaction mixturewas filtered through a pad of celite (rinsed with EtOAc). The filtratewas then evaporated in vacuo. The residue was purified by MDAP (HpH).Desired fractions were combined and evaporated under vacuum to afford awhite solid. The solid was dissolved in DCM, loaded onto a 10 g SNAPcartridge and purified by column chromatography using a gradient 0-100%of ethyl acetate in cyclohexane. Desired fractions were combined andevaporated under vacuum to afford the product as a colourless solid (1.7mg). LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=322.

Example 117:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 118, 56.4 mg, 0.230 mmol),2-chloro-6-methylpyridine (0.022 mL, 0.276 mmol), Pd₂(dba)₃ (10.53 mg,0.011 mmol), sodium tert-butoxide (33.1 mg, 0.345 mmol), DavePhos (9.05mg, 0.023 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was thenheated and stirred at 100° C. for 4 h. After cooling to rt, the reactionmixture was filtered through a pad of celite (rinsed with EtOAc). Thefiltrate was then evaporated in vacuo. The residue was purified by MDAP(HpH). Desired fractions were combined and evaporated under vacuum toafford the product as a white solid (5.9 mg).

LCMS (2 min Formic): Rt=0.50 min, [MH]⁺=337

Example 118:rac-1-((2S,3R,4R)-3-methyl-4-(phenylamino)-2-propyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone

To a 0.5-2 mL vial containing a suspension ofrac-1-((2S,3R,4R)-4-Amino-3-methyl-2-propyl-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)ethanone(for a preparation see Intermediate 122, 50 mg, 0.202 mmol), DavePhos (9mg, 0.023 mmol), Pd₂dba₃ (10 mg, 10.92 μmol) and sodium tert-butoxide(20 mg, 0.208 mmol) in anhydrous 1,4-dioxane (1.5 mL) was addedbromobenzene (26 μl, 0.247 mmol). The vial was sealed and the solutionwas bubbled with nitrogen for 10 min. The reaction mixture was heated ina microwave using settings as to maintain a temperature of 110° C. for45 min. After cooling, the reaction mixture was filtered through a layerof celite, washing through with EtOAc. The solvent was removed by rotaryevaporation leaving a yellow residue which was purified by MDAP (HpH).The appropriate fractions were combined and the solvent was removed byrotary evaporation to give the product as a colourless oil whichsolidified (4.8 mg, 0.015 mmol, 7%).

LCMS (2 min Formic): Rt=0.89 min, [MH]⁺=324.

Example 119:rac-1-((2S,3S,4R)-2-cyclopropyl-3-methyl-4-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a flask containingrac-1-((2S,3S,4S)-2-cyclopropyl-4-hydroxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 124a, 35 mg, 0.143 mmol) intetrahydrofuran (THF) (1 mL) was added phenol (13.70 mg, 0.146 mmol) andtriphenylphosphine (37.4 mg, 0.143 mmol) at rt. DIAD (0.03 mL, 0.143mmol) was added and the reaction was stirred for 10 min at rt. Furtherphenol (13.7 mg, 0.146 mmol) was added and the reaction stirred forafurther 1.5 h and then allowed to stand overnight. Further phenol (13.7mg, 0.146 mmol) was added, followed by triphenylphosphine (23 mg) andDIAD (14 uL). The reaction was allowed to stir for 1.5 h. The reactionmixture was partitioned between water (20 mL) and EtOAc (20 mL). Thelayers were separated and the aqueous phase washed with further EtOAc.The combined organics were dried (Na₂SO₄) and concentrated in vacuo toafford the crude product as a yellow oil. This was dissolved in DCM andpurified by flash chromatography on a silica cartridge (10 g). It waseluted with 0-60% EtOAc/cyclohexane. The appropriate fractions wereconcentrated in vacuo to yield the desired product as a pale yellow oil.This was taken up in DMSO/MeOH (1:1) and further purified by MDAP (HpH).The appropriate fractions were concentrated in vacuo to afford thedesired product as a colourless oil (7 mg, 0.023 mmol, 16%). LCMS (2 minFormic): Rt=1.29 min, MH+=322.

Example 120:rac-1-((2S,3S,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3S,4R)-2-cyclopropyl-4-hydroxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 124b, 50 mg, 0.204 mmol) wasdissolved in N,N-dimethylformamide (DMF) (1 mL) at rt. Sodium hydride(20 mg, 0.51 mmol) was then added in 1 portion and the reaction stirredat rt for 10 min. 2-Fluoro-6-methylpyridine (68 mg, 0.611 mmol) wasadded drop-wise and the reaction mixture heated at 70° C. for ˜2 h. Thereaction was quenched by the addition of H₂O (10 mL). The organics wereextracted into Et₂O (20 mL) and the aqueous layer further extracted withEt₂O (2×20 mL). The combined organics were then washed with further H₂O(2×20 mL), dried (Na₂SO₄) and concentrated in vacuo to afford the crudeproduct as a colourless oil. This was taken up in DCM and added to a 10g silica cartridge. This was purified by flash chromatography, elutingwith 0-50% EtOAc/cyclohexane. The appropriate fractions wereconcentrated in vacuo to afford the desired product as a white solid (18mg, 0.054 mmol, 27%).

LCMS (2 min Formic): Rt=1.34 min, [MH]⁺=336.

Example 121:rac-1-((2S,3R,4R)-2,3-dimethyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a test tube were addedrac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 6, 47.3 mg, 0.217 mmol),2-bromopyridine (0.025 mL, 0.260 mmol), Pd₂(dba)₃ (9.92 mg, 10.83 μmol),sodium tert-butoxide (31.2 mg, 0.325 mmol), DavePhos (8.53 mg, 0.022mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was then heated andstirred at 100° C. in a greenhouse reactor for 3 h. After cooling to rt,the reaction mixture was filtered through a pad of celite (rinsed withEtOAc). The filtrate was then evaporated in vacuo. The residue waspurified by MDAP (Formic). The desired fractions were combined andevaporated in vacuo to afford the desired product as a colourless solid(47.9 mg).

LCMS (2 min formic): Rt=0.54 min, [MH]⁺=296.

Example 122:rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The 2-bromo-6-methylpyridine (0.355 mL, 3.10 mmol),rac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 10, 360 mg, 1.550 mmol), Dave Phos(60.9 mg, 0.155 mmol), Pd₂(dba)₃ (85 mg, 0.093 mmol), sodiumtert-butoxide (208 mg, 2.169 mmol) and 1,4-dioxane (10 mL) were placedin a round bottomed flask and allowed to stir at 100° C. for 4 h. Thereaction was allowed to stir at 100° C. for a further 18 h, and thentreated with more Pd₂(dba)₃ (85 mg, 0.093 mmol) and DavePhos (60.9 mg,0.155 mmol) and allowed to stir at 100° C. for 24 h. The reaction waspartitioned between water and EtOAc, the organic layer was washed withbrine, dried using a hydrophobic frit and concentrated to a brown solid.This solid was purified using a 25 g silica column, elute: 0-50%EtOAc:cyclohexane. Clean fractions were combined and concentrated toleave the product as a light brown solid (167 mg).

LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=324.

Example 123:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methyloxazol-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of cyanogen bromide (21.68 mg, 0.205 mmol) and sodiumcarbonate (43.4 mg, 0.409 mmol) in THE (2 mL) at −20° C. was addedrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(For a preparation see Intermediate, 50 mg, 0.205 mmol). The mixture wasstirred at −20° C. for 2 hr then allowed to warm to rt, further cyanogenbromide (21.68 mg, 0.205 mmol) added and stirred for 18 hr. The reactionmixture was filtered. To the filtrate was added water (2 mL),1-hydroxypropan-2-one (0.028 mL, 0.41 mmol) and 1M NaOH (0.2 mL) and thereaction heated to 120° C. for 3 h in a microwave reactor. The reactionmixture was diluted with water and extracted with diethyl ether (2×30mL). The combined organics were washed with brine, dried (MgSO₄) andevaporated to give crude product. The samples were purified by MDAP(HpH) to afford the product (7 mg) as a clear oil. LCMS (2 min HpH):Rt=0.94 min, [MH]⁺=326.

Example 124:rac-1-((2S,3R,4R)-4-((3-(aminomethyl)phenyl)amino)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone,hydrochloride

rac-tert-Butyl3-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzylcarbamate(for a preparation see Intermediate 127, 165 mg, 0.367 mmol) wasdissolved in methanol (1 mL) and treated with 4M hydrochloric acid (3mL, 12.00 mmol) in 1,4-dioxane. The reaction was stirred at rt for 3 h.The solvent and excess HCl were removed under reduced pressure. Theresidue was loaded on to a 5 g SCX cartridge and washed with DCM andthen MeOH. The product was eluted with 2M NH₃ in MeOH and this basicfiltrate was concentrated to leave the crude. Purification wasundertaken using MDAP (Formic). Evaporation of the collected fractionsgave the product. This was dissolved in DCM (0.5 mL) and treated with 1MHCl in Et₂O (0.1 mL). The resulting solid was triturated and the solventwas carefully pipetted off. The resulting solid was dried in the vacoven to leave the product HCl salt as a tan solid (28 mg).

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=350.

Example 125:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N,N-dimethylbenzamide

Pd₂(dba)₃ (37.6 mg, 0.041 mmol), DavePhos (32.3 mg, 0.082 mmol), sodiumtert-butoxide (59.2 mg, 0.616 mmol) and 4-bromo-N,N-dimethylbenzamide(94 mg, 0.411 mmol) were all added to a 0.5-2.0 mL microwave vial. Tothis was addedrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 50.2 mg, 0.205 mmol) in1,4-dioxane (2 mL). The vessel was sealed and, following stirring of thereaction mixture, was heated in a microwave heater at 120° C. for 40min. The reaction mixture was filtered through a 2.5 g celite cartridge,washed through with ethyl acetate, and concentrated in vacuo to give adark yellow oil. The crude residue was taken up in dichloromethane andloaded onto a 25 g silica flash column, and eluted in 60-100% ethylacetate in cyclohexane. The appropriate fractions were collected andconcentrated in vacuo to afford a pale yellow crystalline powder (59.1mg, 66.1%).

LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=392.

Example 126:rac-1-((2S,3R,4R)-4-((5-chloropyridin-2-yl)amino)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-1-((2S,3R,4R)-4-Amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 14, 205 mg, 0.839mmol) was added to a reaction vessel in anhydrous 1,4-dioxane (5 mL).2-bromo-5-chloropyridine (242 mg, 1.259 mmol), DavePhos (66.0 mg, 0.168mmol), sodium tert-butoxide (242 mg, 2.52 mmol) and Pd₂(dba)₃ (115 mg,0.126 mmol) were added and the reaction left to stir at 100° C. for 1 hunder N₂. The reaction mixture was filtered through celite and thecelite washed with ethyl acetate (3×10 mL). The combined filtrates werewashed with water (2×40 mL) and the layers separated. The organic phasewas dried through a hydrophobic frit and concentrated in vacuo to give665 mg of crude orange/brown solid. This was purified by chromatographyon silica (25 g, eluting with 0-2.5% methanolic ammonia/DCM). Thefractions containing product were combined and concentrated in vacuo togive 256 mg of product as an orange solid. This was still ofinsufficient purity so was purified by chromatography on silica (10 g,eluting with 0-25% ethyl acetate/cyclohexane). The fractions containingmainly product were combined and concentrated in vacuo to give 160 mg ofproduct (160 mg, 0.450 mmol, 53.6%) as an orange solid. The fractionscontaining product with a substantial impurity were combined andconcentrated in vacuo to give 139 mg of impure product (139 mg, 0.391mmol, 46.6%) as an orange solid. LCMS (2 min Formic): Rt=1.06 min,[MH]⁺=356.

Example 127:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoicacid

A sample of rac-methyl4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate(for a preparation see Intermediate 128, 66 mg, 0.174 mmol) wasdissolved in acetonitrile (1 mL), and to this was added sodium hydroxide(2M) (0.5 mL, 1.0 mmol). The mixture was stirred at 60° C. for 90 min.The mixture continued to stir at 60° C. for 2 h 30 min. The mixturecontinued to stir at 60° C. for a further 68 h. The mixture continued tostir at 60° C. and 0.25 mL sodium hydroxide (2M) was added, and themixture continued to stir at 60° C. The reaction did not proceedfurther. A further 0.75 mL sodium hydroxide (2M) and 0.25 mLacetonitrile was added, and the mixture stirred at 80° C. for 2 h. Themixture was allowed to cool to rt, neutralised with 2M hydrochloricacid, and extracted into ethyl acetate. The aqueous layer was washed afurther 2 times with ethyl acetate, the organic layers combined andconcentrated in vacuo to afford a dark yellow oil. The residue was takenup in 1:1 MeOH:DMSO 1 mL and purified by MDAP (Formic). The solvent wasevaporated in vacuo to give the required product (10.6 mg).

LCMS (2 min Formic): Rt=0.94 min, [M−H]⁻=363.

Example 128:rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-2-methylnicotinonitrile

To a dried flask under nitrogen was addedrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14 50 mg, 0.205 mmol),6-bromo-2-methylnicotinonitrile (48.4 mg, 0.246 mmol), DavePhos (32.2mg, 0.082 mmol), Pd₂(dba)₃ (37.5 mg, 0.041 mmol) and sodiumtert-butoxide (59.0 mg, 0.614 mmol). To this was added 1,4-dioxane (4mL), and the solution was degassed with nitrogen for-15 min. The mixturewas then heated for 2 h at 90° C. under nitrogen. A further 33.0 mg of6-bromo-2-methylnicotinonitrile was added, and the mixture continued tostir at 90° C. for a further

2 h under nitrogen. The mixture was allowed to cool to rt, filteredthrough a 2.5 g celite cartridge, washed through with ethyl acetate andconcentrated in vacuo to afford a dark orange oil. The residue was takenup in dichloromethane, loaded onto a 25 g silica flash column and elutedby silica gel chromatography with 5%-40% ethyl acetate in cyclohexane.The appropriate fractions were collected and concentrated in vacuo toafford a yellow oil (26.1 mg, 0.072 mmol, 35.4%).

LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=361.

Example 129:rac-2-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrimidine-5-carbonitrile

rac-1-((2S,3R,4R)-4-Amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 14, 48 mg, 0.196 mmol) was dissolvedin dimethyl sulfoxide (DMSO) (1.5 mL) and transferred to a 0.5-2.0 mLmicrowave vessel. To this was added 2-chloropyrimidine-5-carbonitrile(54.8 mg, 0.393 mmol) and DIPEA (0.103 mL, 0.589 mmol). The vessel wassealed and the reaction heated on a microwave heater to 200° C. for 1 h.The reaction mixture was dissolved in 1:1 MeOH:DMSO (1 mL) and purifiedby MDAP (HpH). The solvent was evaporated in vacuo to give the requiredproduct (19.8 mg). LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=348.

Example 130:rac-1-((2S,3R,4R)-2,3-diethyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a microwave vial containing a solution ofrac-1-((2S,3R,4R)-4-amino-2,3-diethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 133, 42 mg, 0.170 mmol) was added2-bromo-6-methylpyridine (0.039 mL, 0.341 mmol) and sodium tert-butoxide(49.2 mg, 0.511 mmol) and the vial evacuated and back filled with N₂(×2). To this was added DavePhos (26.8 mg, 0.068 mmol) and Pd₂(dba)₃(31.2 mg, 0.034 mmol) and the reaction mixture then heated at 120° C.for 40 min in a microwave heater. The reaction mixture was passedthrough a 2.5 g celite cartridge and washed with EtOAc (30 mL). Thefiltrate was concentrated in vacuo and the crude material dissolved indichloromethane. This crude material was loaded onto a 10 g silica flashcolumn, and purified by flash chromatography, eluting with 0%-40% ethylacetate in cyclohexane. The appropriate fractions were combined andconcentrated in vacuo to afford the product as a yellow oil (57 mg,0.169 mmol, 99%). A 7.4 mg sample was retained in case furtherpurification was unsuccessful. The remainder was taken up in 0.9 mLDMSO/MeOH (1:1) and purified by MDAP (HpH). The appropriate fractionswere collected and concentrated in vacuo to afford the desired productas a colourless oil (31 mg, 0.092 mmol, 53.9%).

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=338.

Example 131:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

To a reaction vessel sodium tert-butoxide (838 mg, 8.72 mmol), Pd₂(dba)₃(300 mg, 0.327 mmol), DavePhos (172 mg, 0.436 mmol), andrac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 195, 690 mg, 2.181 mmol) were addedin 1,4-dioxane (25 mL). 2-Bromo-6-methylpyridine (0.372 mL, 3.27 mmol)was added and the reaction left to stir for 2.5 h under nitrogen at 100°C. The reaction mixture was left to cool to rt and then filtered throughcelite and the celite washed with ethyl acetate (2×30 mL). The combinedfiltrates were concentrated in vacuo to give 1.109 g of crude product.This was purified by chromatography on silica (50 g, eluting with 2Mammonia in methanol/DCM 0-20%). The fractions containing product werecombined and concentrated in vacuo to give 303 mg of the product as ayellow/brown solid. 30 mg of this was dissolved in 1:1 MeOH:DMSO 1 mLand purified by MDAP (Formic). The solvent was evaporated in vacuo togive 4 mg of the product.

LCMS (2 min formic): Rt=0.62 min, [MH]⁺=380.

Example 132:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,N,3-trimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vesselrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonylchloride (for a preparation see Intermediate 196, 117 mg, 0.294 mmol) inanhydrous acetonitrile (3 mL) was added. The vessel was put under aninert atmosphere (N₂) and the solution left to stir. Dimethylaminehydrochloride (620 mg, 7.60 mmol) was dissolved in acetonitrile (12 mL)and DIPEA (2.260 mL, 12.94 mmol) was added, this solution was addedslowly to the stirring solution The reaction mixture was left to stir atrt for 1 h. The solution was concentrated in vacuo and retaken up in DCM(15 mL), this was washed with water (2×15 mL) and separated. The organiclayer was dried and concentrated in vacuo to give 117 mg of anorange/brown solid. This was purified by chromatography on silica (10 g,eluting with 0-8% methanol/DCM over 15 CVs). The fractions containingmostly product were combined and concentrated in vacuo to give 23 mg ofproduct. The fractions containing product with some impurity werecombined and concentrated in vacuo to give 58 mg of less pure product.This second batch was dissolved in 1:1 MeOH:DMSO 1 mL and purified byMDAP (HpH). The solvent was evaporated in vacuo to give 27 mg product.LCMS (2 min formic): Rt=0.61 min, [MH]⁺=406.

Example 133:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel containingrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonylchloride (for a preparation see Intermediate 196 93 mg, 0.234 mmol).Ammonia 0.5M in 1,4-dioxane (10 mL, 5.00 mmol) and DIPEA (0.898 mL, 5.14mmol) were added and the reaction left to stir for 15 min at rt underN₂. This was purified by chromatography on silica (25 g, eluting with0-5% methanol/DCM). The fractions containing product were combined andconcentrated in vacuo to give 13 mg of product as an off white solid.This was insufficiently pure so the column was run again eluting withmethanol/DCM 0-7%. The fractions containing starting material (the acid)were combined and concentrated in vacuo to give 49 mg of recoveredstarting material. Product containing fractions were dissolved in 1:1MeOH:DMSO 1 mL and purified by MDAP (Formic). The pure fractions werecombined and concentrated in vacuo to give 4 mg of product (4 mg, 10.57μmol, 4.52%) as an off white solid.

LCMS (2 min formic): Rt=0.56 min, [MH]⁺=379.

Example 134:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

rac-tert-Butyl(2-(4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate(for a preparation see Intermediate 138, 11.6 mg, 0.020 mmol) wasdissolved in dichloromethane (DCM) (1 mL) in a flask, and sealed. Tothis was carefully added trifluoroacetic acid (250 μL, 3.24 mmol). Themixture was allowed to stir for 2 h at rt. The reaction mixture wasdiluted with dichloromethane and evaporated in vacuo. The residue wastaken up in methanol and loaded onto a 2 g SCX cartridge which had beenpre-wet with methanol. The column was eluted with 3 CVs of methanol,followed by a further 3 CVs of 2M NH₃ in methanol. The methanolicammonia fraction was concentrated in vacuo to afford a colourless glass(10.9 mg, 0.020 mmol, 100%). LCMS (2 min Formic): Rt=0.80 min,[MH]⁺=469.

Example 135:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 140, 70 mg, 0.190 mmol) wasdispensed into a round bottomed flask and treated with DavePhos (7.48mg, 0.019 mmol), Pd₂(dba)₃ (26.1 mg, 0.028 mmol), sodium tert-butoxide(54.8 mg, 0.570 mmol), 1,4-dioxane (12 mL) and the2-bromo-6-methylpyridine (0.044 mL, 0.380 mmol). The reaction wasallowed to stir at 100° C. for 16 h, The reaction was allowed to cool tort and partitioned between water and DCM, the aqueous layer wasextracted with more DCM and the combined organics were washed withbrine, dried using a hydrophobic frit and concentrate to a gum. This waspurified using a 10 g silica column elute: 0-50% EtOAc:cyclohexane.Nothing eluted so the column was run again 0-5% MeOH:DCM one major peakwas eluted and the appropriate fractions were summed and concentrated togive the product but this was still impure Therefore this was furtherpurified using a 10 g silica column elute: 0-5% MeOH:DCM. Theappropriate fractions were summed and concentrated to give the product(48 mg) as a yellow solid. LCMS (2 min formic): Rt=0.70 min, [MH]⁺=460.

Example 136a & 136b:1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(136a) &1-((2R,3S,4S)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(136b)

rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 135, ˜40 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×20 mm Chiralpak IAcolumn eluting with 10% ethanol in heptane at a flow rate of 20 mL/min.Peak 1/Enantiomer A fractions were collected between 21 and 26 min, andPeak 2/Enantiomer B fractions were collected between 32 and 39 min.Fraction solutions were combined and then evaporated to dryness to giveEnantiomer A (12 mg) and Enantiomer B (14 mg) as white solids.

Enantiomer A, Example 136a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IA column elutingwith 15% ethanol in heptane at 1 mL/min—Rt=17.5 min. >99% ee by UV.

Enantiomer B, Example 136b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IA column elutingwith 15% ethanol in heptane at 1 mL/min—Rt=23.5 min, >99% ee by UV.

Example 137:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 140, 70 mg, 0.190 mmol) wasdispensed into a round bottomed flask and treated with DavePhos (7.48mg, 0.019 mmol), Pd₂(dba)₃ (26.1 mg, 0.028 mmol), sodium tert-butoxide(54.8 mg, 0.570 mmol), 1,4-dioxane (12 mL) and the2-bromo-5-methylpyrazine (65.7 mg, 0.380 mmol) the reaction was allowedto stir at 100° C. for 16 h. Further 2-bromo-5-methylpyrazine (65.7 mg,0.380 mmol) was added and the reaction was allowed to stir at 100° C.for 2 h. The reaction was allowed to cool to rt and partitioned betweenwater and DCM, the aqueous layer was extracted with more DCM and thecombined organics were washed with brine, dried using a hydrophobic fritand concentrate to a gum. This was purified using a 10 g silica columnelute: 0-50% EtOAc:cyclohexane. Nothing eluted so the column was runagain 0-5% MeOH:DCM one major peak was eluted and the appropriatefractions were summed and concentrated to give the product but this wasstill impure. Therefore this was further purified using a 10 g silicacolumn, elute:0-5% 2M NH₃/MeOH:DCM, the appropriate fractions weresummed and concentrated to give the product (36 mg) as a yellow solid.

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=461.

Example 138a & 138b:1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(138a) &1-((2R,3S,4S)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(138b)

rac-1-((2S,3R,4R)-2-Cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 137, 38 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm ChiralpakAD-H column eluting with 50% ethanol in heptane at a flow rate of 30mL/min. Peak 1/Enantiomer A fractions were collected between 9 and 12min, and Peak 2/Enantiomer B fractions were collected between 24 and 34min. Fraction solutions were combined and then evaporated to dryness togive Enantiomer A (13 mg) and Enantiomer B (9 mg) as white solids.

Enantiomer A, Example 138a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 50% ethanol in heptane at 1 mL/min—Rt=7.0 min. >99% ee by UV.

This contained ˜10% impurity so was purified further by HPLC on anAtlantis T3 OBD, 150×19 mm, 5 um column using a graduating solventsystem of 10-99% MeCN in 0.1% v/v formic acid/water at a flow rate of 20mL/min. The product eluted at 13.4 min. The desired fractions werecombined and concentrated to leave the product (3.9 mg).

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=461.

Enantiomer B, Example 138b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 50% ethanol in heptane at 1 mL/min—Rt=16.5 min, >99% ee by UV.

Example 139:rac-4-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

A solution ofrac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 143, 82 mg, 0.347 mmol), DavePhos(13.66 mg, 0.035 mmol), 4-bromobenzonitrile (76 mg, 0.416 mmol),Pd₂(dba)₃ (15.89 mg, 0.017 mmol) and sodium tert-butoxide (66.7 mg,0.694 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C.for 5 h. The reaction mixture was allowed to cool to rt, filteredthrough celite and rinsed with ethyl acetate. The solvent was evaporatedin vacuo then dissolved in 1:1 MeOH:DMSO (2×1 mL) and purified MDAP(Formic). The appropriate fractions were combined and concentrated invacuo to give the title compound (50 mg, 0.148 mmol, 43%). LCMS (2 minFormic): Rt=1.01 min, [MH]⁺=338.

Example 140:rac-1-((2S,3R,4R)-6-fluoro-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution ofrac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 143, 97 mg, 0.411 mmol), DavePhos(16.16 mg, 0.041 mmol), 2-bromo-5-methylpyrazine (71.0 mg, 0.411 mmol),Pd₂(dba)₃ (18.80 mg, 0.021 mmol) and sodium tert-butoxide (79 mg, 0.821mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C. for 5h. The reaction mixture was allowed to cool to rt, filtered throughcelite and rinsed with ethyl acetate. The solvent was evaporated invacuo, dissolved in 1:1 MeOH:DMSO and purified by MDAP (HpH). Theappropriate fractions were combined and concentrated in vacuo to givethe title compound (20 mg, 0.061 mmol, 15%). LCMS (2 min Formic):Rt=0.83 min, [MH]⁺=329.

Example 141:rac-1-((2S,3R,4R)-6-fluoro-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution ofrac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 143, 93 mg, 0.394 mmol), DavePhos(15.49 mg, 0.039 mmol), 2-bromo-5-fluoropyridine (69.3 mg, 0.394 mmol),Pd₂(dba)₃ (18.02 mg, 0.020 mmol) and sodium tert-butoxide (76 mg, 0.787mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C. for 5h. The reaction mixture was allowed to cool to rt, filtered throughcelite and rinsed with ethyl acetate. The solvent was evaporated invacuo and the samples were dissolved in 1:1 MeOH:DMSO (1 mL) andpurified by MDAP (HpH). The appropriate fractions were combined andconcentrated in vacuo to give the title compound (32 mg, 0.097 mmol,25%).

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=332.

Example 142:rac-5-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

A solution ofrac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 143, 86 mg, 0.364 mmol),5-chloropyrazine-2-carbonitrile (102 mg, 0.728 mmol) and DIPEA (0.127mL, 0.728 mmol) in NMP (1.5 mL) was heated in a microwave at 200° C. for1 h. The solution was applied directly and purified by MDAP (formic).The appropriate fractions were combined and concentrated in vacuo togive the title compound (30 mg, 0.088 mmol, 24%). LCMS (2 min Formic):Rt=0.88 min, [MH]⁺=340.

Example 143:rac-6-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

A solution ofrac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 143, 90 mg, 0.381 mmol),6-fluoronicotinonitrile (93 mg, 0.762 mmol) and DIPEA (0.133 ml, 0.762mmol) in NMP (1 mL) was heated in the microwave at 200° C. for 30 min.The solution was directly purified by MDAP (Formic). The appropriatefractions were combined and concentrated in vacuo to give the titlecompound (41 mg, 0.121 mmol, 32%).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=339.

Example 144:rac-1-((2S,3R,4R)-6-fluoro-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution ofrac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 143, 85 mg, 0.360 mmol),2-chloro-4-methylpyrimidine (92 mg, 0.719 mmol) and DIPEA (0.126 mL,0.719 mmol) in NMP (1.5 mL) was heated in a microwave at 200° C. for 1h. The solution was purified directly by MDAP (Formic). The appropriatefractions were combined and concentrated in vacuo to give the titlecompound (50 mg, 0.152 mmol, 42%).

LCMS (2 min Formic): Rt=0.79 min, [MH]⁺=329.

Example 145:rac-4-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

A solution ofrac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 143, 80 mg, 0.339 mmol), DavePhos(13.32 mg, 0.034 mmol), 4-bromo-N-methylbenzamide (87 mg, 0.406 mmol),sodium tert-butoxide (65.1 mg, 0.677 mmol) and Pd₂(dba)₃ (15.50 mg,0.017 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C.for 16 h. The reaction mixture was allowed to cool to rt, filteredthrough celite and rinsed with ethyl acetate. The solvent was evaporatedin vacuo and the sample was dissolved in 1:1 MeOH:DMSO (1 mL) andpurified by MDAP (Formic). The appropriate fractions were combined andconcentrated in vacuo to give the title compound (20 mg, 0.054 mmol,16%).

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=370.

Example 146a & 146b:1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(146a) &1-((2R,3S,4S)-2-ethyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(146b)

rac-1-((2S,3R,4R)-2-Ethyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 61, ˜130 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm ChiralpakAD-H column eluting with 5% ethanol in heptane at a flow rate of 30mL/min. Peak 1/Enantiomer A fractions were collected between 7 and 9min, and Peak 2/Enantiomer B fractions were collected between 10.5 and12.5 min. Fraction solutions were combined and then evaporated todryness to give Enantiomer A (63 mg) and Enantiomer B (60 mg) as whitesolids.

Enantiomer A, Example 146a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 5% ethanol in heptane at 1 mL/min—Rt=7.0 min. >99% ee by UV.

Enantiomer B, Example 146b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 5% ethanol in heptane at 1 mL/min—Rt=10.3 min, >99% ee by UV.

Example 147a & 147b:4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile(147a) &4-(((2R,3S,4S)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile(147b)

rac-4-(((2S,3R,4R)-1-Acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile(for a preparation see Example 62, ˜70 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm ChiralpakOD-H column eluting with 10% ethanol in heptane at a flow rate of 30mL/min. Peak 1/Enantiomer A fractions were collected between 12 and 14min, and Peak 2/Enantiomer B fractions were collected between 15.5 and17.5 min. Fraction solutions were combined and then evaporated todryness to give Enantiomer A (29 mg) and Enantiomer B (29 mg) as whitesolids.

Enantiomer A, Example 147b

Analytical Chiral HPLC using a 250×4.6 mm Chiralcel OD-H column elutingwith 10% ethanol in heptane at 1 mL/min—Rt=10 min. >99% ee by UV.

Enantiomer B, Example 147a

Analytical Chiral HPLC using a 250×4.6 mm Chiralcel OD-H column elutingwith 10% ethanol in heptane at 1 mL/min—Rt=12 min, >96% ee by UV.

Example 148:rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel 2-bromo-4-methylpyrimidine (159 mg, 0.919 mmol),rac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 115 mg, 0.459 mmol), sodiumtert-butoxide (132 mg, 1.378 mmol), in 1,4-dioxane (5 mL) were added.The solution was treated with Pd₂(dba)₃ (63.1 mg, 0.069 mmol) andDavePhos (36.2 mg, 0.092 mmol) and left to stir at 100° C. for 16 hunder N₂. The reaction mixture was filtered through celite and thecelite washed with ethyl acetate (2×20 mL). The combined filtrates werewashed with water (2×35 mL+10 ml brine added to each wash) and passedthrough a hydrophobic frit before being concentrated in vacuo to give615 mg of crude orange gum. This was purified by chromatography onsilica (25 g, eluting with 0-100% ethyl acetate/cyclohexane). Thefractions containing product were combined and concentrated in vacuo togive 41 mg of product as an orange solid. The sample was dissolved in1:1 MeOH:DMSO 1 mL and purified by MDAP (Formic). The solvent wasevaporated in vacuo to give 18 mg of product (18 mg, 0.053 mmol, 11.44%)as a white solid. LCMS (2 min formic): Rt=0.86 min, [MH]⁺=343.

Example 149:rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-4-((5-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 100 mg, 0.400 mmol),2-bromo-5-fluoropyridine (105 mg, 0.599 mmol), Pd₂(dba)₃ (54.9 mg, 0.060mmol), sodium tert-butoxide (115 mg, 1.199 mmol) and DavePhos (15.72 mg,0.040 mmol) were suspended in 1,4-dioxane (10 mL) and allowed to stir at100° C. for 4 h. The reaction was filtered through celite andconcentrated to a oil, this oil was purified using a MDAP (Formic) togive a solid which was eluted through a NH₂ SPE (5 g) with MeOH, theeluent was concentrated and dried to give the product (58 mg, 0.168mmol, 42.0%) as a orange solid.

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=346.

Example 150:rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

Therac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 100 mg, 0.400 mmol)4-bromobenzonitrile (109 mg, 0.599 mmol), Pd₂(dba)₃ (54.9 mg, 0.060mmol), sodium tert-butoxide (115 mg, 1.199 mmol) and DavePhos (15.72 mg,0.040 mmol) were suspended in 1,4-dioxane (10 mL) and allowed to stir at100° C. for 4 h. The reaction was filtered through celite andconcentrated to a oil, this oil was purified using a MDAP (HpH) to givea solid which was eluted through a NH₂ SPE (5 g) with MeOH, the eluentwas concentrated and dried to give the product (50 mg, 0.142 mmol,35.6%) as a yellow solid.

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=352.

Example 151:rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

Therac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 100 mg, 0.400 mmol)4-bromo-N-methylbenzamide (128 mg, 0.599 mmol), Pd₂(dba)₃ (54.9 mg,0.060 mmol), sodium tert-butoxide (115 mg, 1.199 mmol) and DavePhos(15.72 mg, 0.040 mmol) were suspended in 1,4-dioxane (10 mL) and allowedto stir at 100° C. for 16 h, the reaction was treated with furtherPd₂(dba)₃ (54.9 mg, 0.060 mmol) and allowed to stir at 100° C. for afurther 5 h. The reaction was allowed to cool to rt and was filteredthrough celite and concentrated to a gum. This gum was purified using aMDAP (Formic) to give a solid, this solid was eluted through a NH₂ SPE(5 g) with MeOH, the eluent was concentrated and dried to give theproduct (28 mg, 0.073 mmol, 18.28%) as an off-white solid.

LCMS (2 min Formic): Rt=0.88 min, [MH]⁺=384.

Example 152:rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 100 mg, 0.400 mmol)2-bromo-6-methoxypyridine (113 mg, 0.599 mmol), Pd₂(dba)₃ (54.9 mg,0.060 mmol), sodium tert-butoxide (115 mg, 1.199 mmol) and DavePhos(15.72 mg, 0.040 mmol) were suspended in 1,4-dioxane (10 mL) and allowedto stir at 100° C. for 16 h. The reaction was allowed to cool to rt andwas filtered through celite and concentrated to a gum. This gum waspurified using a MDAP (Formic) to give a solid, this solid was elutedthrough a NH₂ SPE (5 g) with MeOH, the eluent was concentrated and driedto the product (49 mg, 0.137 mmol, 34.3%) as an off-white solid. LCMS (2min Formic): Rt=1.11 min, [MH]⁺=358.

Example 153:rac-6-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

Therac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 100 mg, 0.400 mmol),6-fluoronicotinonitrile (98 mg, 0.799 mmol), DIPEA (0.140 mL, 0.799mmol) and N-methyl-2-pyrrolidone (NMP) (2 mL) were placed in amicrowaveable vial and irradiated in a microwave at 200° C. for 2.5 h.The reaction was purified directly using a MDAP (Formic) to give asolid, this solid was eluted through a NH₂ SPE (5 g) with MeOH, theeluent was concentrated and dried to give the product (29 mg, 0.082mmol, 20.60%) as a off white solid. LCMS (2 min Formic): Rt=0.96 min,[MH]⁺=353.

Example 154:rac-5-(((2S,3R,4R)-1-acetyl-2-ethyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

Therac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 100 mg, 0.400 mmol),5-chloropyrazine-2-carbonitrile (111 mg, 0.799 mmol), DIPEA (0.140 mL,0.799 mmol) and N-methyl-2-pyrrolidone (NMP) (2 mL) were placed in amicrowaveable vial and irradiated in a microwave at 200° C. for 2.5 h.The reactions purified directly using a MDAP (Formic) to give a solid,this solid was eluted through a NH₂ SPE (5 g) with MeOH, the eluent wasconcentrated and dried to give the product (77 mg, 0.218 mmol, 54.5%) asan orange solid. LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=354.

Example 155:rac-1-((2S,3R,4R)-2-ethyl-6-fluoro-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-ethyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 40, 100 mg, 0.400 mmol),2-chloro-5-methylpyrazine (77 mg, 0.599 mmol), Pd₂(dba)₃ (54.9 mg, 0.060mmol), sodium tert-butoxide (115 mg, 1.199 mmol) and DavePhos (15.72 mg,0.040 mmol) were suspended 1,4-dioxane (10 mL) and allowed to stir at100° C. for 18 h. The reaction was allowed to cool to rt and werefiltered through celite and concentrated to a gum. This gum was purifiedusing a MDAP (Formic) to give a solid, this solid was eluted through aNH₂ SPE (5 g) with MeOH, the eluent was concentrated and dried to givethe product (50 mg, 0.146 mmol, 36.6%) as an off-white solid. LCMS (2min Formic): Rt=0.89 min, [MH]⁺=343.

Example 156:rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 146, 100 mg, 0.381mmol), 6-fluoronicotinonitrile (93 mg, 0.762 mmol), DIPEA (0.133 mL,0.762 mmol) and N-methyl-2-pyrrolidone (NMP) (2 mL) were irradiated in amicrowave at 200° C. for 1 h. The reaction was purified directly using aMDAP (Formic) to give a solid. This solid was eluted through a NH₂ SPE(5 g) with MeOH, the eluent was concentrated and dried to give theproduct (73 mg, 0.200 mmol, 52.5%) as an off-white solid.

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=365.

Example 157:rac-5-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 146, 100 mg, 0.381 mmol),5-chloropyrazine-2-carbonitrile (106 mg, 0.762 mmol) DIPEA (0.133 mL,0.762 mmol) and N-methyl-2-pyrrolidone (NMP) (2 mL) were irradiated in amicrowave at 200° C. for 30 min, the reaction was purified directlyusing a MDAP (Formic) to give a solid. This solid was eluted through aNH₂ SPE (5 g) with MeOH, the eluent was concentrated and dried to givethe product (72 mg, 0.197 mmol, 51.7%) as a brown solid. LCMS (2 minFormic): Rt=0.96 min, [MH]⁺=366.

Example 158:rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 146, 100 mg, 0.381 mmol),2-chloro-4-methylpyrimidine (98 mg, 0.762 mmol) DIPEA (0.133 mL, 0.762mmol) and N-methyl-2-pyrrolidone (NMP) (2 mL) were irradiated in amicrowave at 200° C. for 2.5 h, the reaction was purified directly usinga MDAP (Formic) to give a solid. This solid was eluted through a NH₂ SPE(5 g) with MeOH, the eluent was concentrated and dried to the product(13 mg, 0.037 mmol, 9.62%) as a light brown solid. LCMS (2 min Formic):Rt=0.90 min, [MH]⁺=355.

Example 159:rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 146, 100 mg, 0.381mmol), 2-bromo-5-methylpyrazine (99 mg, 0.572 mmol), Pd₂(dba)₃ (52.4 mg,0.057 mmol), sodium tert-butoxide (110 mg, 1.144 mmol) and DavePhos(15.00 mg, 0.038 mmol), were suspended in 1,4-dioxane (10 mL) andallowed to stir at 100° C. for 4 h. The reaction was filtered throughcelite and concentrated to an oil. This oil was purified using a MDAP(Formic) to give a solid which was eluted through a NH₂ SPE (5 g) withMeOH, the eluent was concentrated and dried to give the product (26 mg,0.073 mmol, 19.24%) as a yellow solid. LCMS (2 min Formic): Rt=0.92 min,[MH]⁺=355.

Example 160:rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((5-fluoropyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 146, 100 mg, 0.381mmol), 2-bromo-5-fluoropyridine (101 mg, 0.572 mmol), Pd₂(dba)₃ (52.4mg, 0.057 mmol), sodium tert-butoxide (110 mg, 1.144 mmol) and DavePhos(15.00 mg, 0.038 mmol), were suspended in 1,4-dioxane (10 mL) andallowed to stir at 100° C. for 20 h. The reaction was filtered throughcelite and concentrated to an oil. This oil was purified using a MDAP(Formic) to give a solid which was eluted through a NH₂ SPE (5 g) withMeOH, the MeOH was concentrated and dried to give the product (6 mg,0.017 mmol, 4.40%).

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=358.

Example 161:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 146, 100 mg, 0.381 mmol),4-bromobenzonitrile (104 mg, 0.572 mmol), Pd₂(dba)₃ (52.4 mg, 0.057mmol), sodium tert-butoxide (110 mg, 1.144 mmol) and DavePhos (15.00 mg,0.038 mmol), were suspended in 1,4-dioxane (10 mL) and allowed to stirat 100° C. for 4 h. The reaction was filtered through celite andconcentrated to a oil. This oil was purified using a MDAP (Formic) togive a solid which was eluted through a NH₂ SPE (5 g) with MeOH, theeluent was concentrated and dried to give the product (30 mg, 0.083mmol, 21.65%) as a white solid. LCMS (2 min Formic): Rt=1.09 min,[MH]⁺=364.

Example 162:rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 146, 100 mg, 0.381 mmol),2-bromo-6-methylpyridine (98 mg, 0.572 mmol), Pd₂(dba)₃ (52.4 mg, 0.057mmol), sodium tert-butoxide (110 mg, 1.144 mmol) and DavePhos (15.00 mg,0.038 mmol) were suspended in 1,4-dioxane (10 mL). The reactions wereallowed to stir at 100° C. for 16 h. The reaction was allowed to cool tort and was filtered through celite and concentrated to a gum. This gumwas purified using a MDAP (Formic) to give a solid which was elutedthrough a NH₂ SPE (5 g) with MeOH, the eluent was concentrated and driedto give the product (36 mg, 0.102 mmol, 26.7%).

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=354.

Example 163:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 146, 100 mg, 0.381 mmol)4-bromo-N-methylbenzamide (122 mg, 0.572 mmol), Pd₂(dba)₃ (52.4 mg,0.057 mmol), sodium tert-butoxide (110 mg, 1.144 mmol) and DavePhos(15.00 mg, 0.038 mmol) were suspended in 1,4-dioxane (10 mL). Thereaction was allowed to stir at 100° C. for 16 h. The reaction wasallowed to cool to rt and was filtered through celite and concentratedto a gum. This gum was purified using a MDAP (Formic) to give a solidwhich was eluted through a NH₂ SPE (5 g) with MeOH, the eluent wasconcentrated and dried to give the product (9 mg, 0.023 mmol, 5.97%).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=396.

Example 164:rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 146, 100 mg, 0.381mmol) 2-bromo-6-methoxypyridine (108 mg, 0.572 mmol), Pd₂(dba)₃ (52.4mg, 0.057 mmol), sodium tert-butoxide (110 mg, 1.144 mmol) and DavePhos(15.00 mg, 0.038 mmol) were suspended in 1,4-dioxane (10 mL) and allowedto stir at 100° C. for 16 h. The reaction was allowed to cool to rt andwas filtered through celite and concentrated to a gum. This gum waspurified using a MDAP (Formic) to give a solid which was eluted througha NH₂ SPE (5 g) with MeOH, the eluent was concentrated and dried to givethe product (69 mg, 0.187 mmol, 49.0%). LCMS (2 min Formic): Rt=1.14min, [MH]⁺=370.

Example 165:rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 164, 63 mg, 0.171 mmol) and sodium iodide(128 mg, 0.853 mmol) were suspended in acetonitrile (10 mL), TMSCl(0.044 mL, 0.341 mmol) was added portion-wise and the reaction wasallowed to stir at 60° C. under reflux conditions for 16 h. The reactionwas allowed to cool to rt and was concentrated to a solid, this solidwas partitioned between 1M NaOH and DCM, the organic layer was washedwith 10% Na₂S₂O₃ (aq) dried using a hydrophobic frit and concentrated toa brown solid. This solid was purified using a MDAP (Formic) to give ayellow solid, this solid was eluted through a NH₂ SPE (1 g) with MeOH,the eluent was concentrated and dried to give the product (8 mg, 0.023mmol, 13.20%) as a pale red solid. LCMS (2 min Formic): Rt=0.78 min,[MH]⁺=356.

Example 166:rac-5-(((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.rac-1-((2S,3R,4R)-4-amino-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 150, 23.3 mg, 0.078 mmol) inN-methyl-2-pyrrolidone (NMP) (0.7 mL) was then added. To this was added5-chloropyrazine-2-carbonitrile (21.65 mg, 0.155 mmol), and DIPEA (0.041mL, 0.233 mmol) and the resultant solution then heated to 150° C. for 30min in a microwave. The reaction mixture was filtered through a cottonwool plug directly into an LCMS vial and was then purified by MDAP(Formic). The appropriate fraction was collected and concentrated invacuo to afford the desired product as a yellow gum which was stillimpure. Therefore the crude product was taken up in DCM and loaded ontoa silica cartridge (10 g). This was purified by flash chromatography,eluting with 0-100% EtOAc/cyclohexane. The appropriate fractions werecollected and concentrated in vacuo to afford the desired product as acolourless oil (6.3 mg, 0.016 mmol, 20.13%). LCMS (2 min Formic):Rt=0.90 min, [MH]⁺=404.

Example 167:rac-1-((2S,3R,4)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.1-((2S,3R,4R)-4-Amino-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 150, 23 mg, 0.077 mmol) in1,4-dioxane (0.75 mL) was then added. To this was added2-bromo-5-methylpyrazine (0.017 mL, 0.153 mmol), sodium tert-butoxide(14.72 mg, 0.153 mmol) and DavePhos (6.03 mg, 0.015 mmol) and theresultant suspension then had N₂ bubbled through it for ˜5 min.Pd₂(dba)₃ (14.02 mg, 0.015 mmol) was added and N₂ was bubbled throughthe reaction mixture for a further ˜5 min. The reaction was then heatedto 100° C. for 30 min in a microwave. The reaction was then re-heated to100° C. for a further 30 min. The reaction mixture was then diluted withEtOAc and filtered though celite (2.5 g). The celite was washed withfurther EtOAc (2×10 mL) and the resultant solution concentrated invacuo. This was taken up in MeOH/DMSO (1:1, 0.9 mL) and purified by MDAP(Formic). The appropriate fraction was collected and concentrated invacuo to afford a colourless gum (3.3 mg, 8.41 μmol, 10.98%).

LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=393.

Example 168:rac-1-((2S,3R,4R)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 0.5-2 mL microwave vial was evacuated and back filled with N₂.rac-1-((2S,3R,4R)-4-Amino-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 150, 100 mg, 0.333 mmol) inN-methyl-2-pyrrolidone (NMP) (1.6 mL) was then added. To this was added2-chloro-4-methylpyrimidine (86 mg, 0.666 mmol), and DIPEA (0.174 mL,0.999 mmol) and the resultant solution then heated to 200° C. for 30 minin a microwave. The reaction mixture was then heated to 200° C. in amicrowave for a further 30 min. The reaction mixture was filteredthrough a cotton wool plug directly into two LCMS vials and was thenpurified by 2×MDAP (Formic). The appropriate fractions were collectedand concentrated in vacuo to afford the desired product as a yellow oil(7.8 mg, 0.020 mmol, 5.97%).

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=393.

Example 169:rac-6-(((2S,3R,4R)-1-acetyl-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

A solution ofrac-1-((2S,3R,4R)-4-amino-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 150, 101 mg, 0.336 mmol) in NMP (1mL) was treated with DIPEA (0.061 mL, 0.350 mmol) and6-fluoronicotinonitrile (43 mg, 0.352 mmol) then heated at 150° C. for 1h using a microwave reactor. Crude product was purified directly by MDAP(HpH) and appropriate fractions combined then concentrated under reducedpressure to give the desired product as a white foamy solid (70 mg).

LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=403.

Example 170:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel 2-bromo-6-methylpyridine (0.028 mL, 0.248 mmol),rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for preparation see Intermediate 152, 37.5 mg, 0.124 mmol), sodiumtert-butoxide (35.8 mg, 0.372 mmol), in 1,4-Dioxane (5 mL) were added.The solution was treated with Pd₂(dba)₃ (17.03 mg, 0.019 mmol) andDavePhos (9.76 mg, 0.025 mmol) and left to stir at 100° C. for 2 h underN₂. The reaction mixture was allowed to cool to rt and was then filteredthrough celite and the celite washed with ethyl acetate. The combinedfiltrates were concentrated in vacuo to give a crude orange/brown gum.This gum was purified by MDAP (Formic) to give an off-white solid. Thissolid was eluted through a NH₂ SPE (5 g) with MeOH, the eluent wasconcentrated to give the product (18 mg, 0.046 mmol, 36.9%) as anoff-white solid. LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=394.

Example 171:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel 2-bromo-4-methylpyrimidine (42.9 mg, 0.248 mmol),rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for preparation see Intermediate 152, 37.5 mg, 0.124 mmol), sodiumtert-butoxide (35.8 mg, 0.372 mmol), in 1,4-dioxane (5 mL) were added.The solution was treated with Pd₂(dba)₃ (17.03 mg, 0.019 mmol) andDavePhos (9.76 mg, 0.025 mmol) and left to stir at 75° C. for 72 h underN₂. The reaction was treated with further sodium tert-butoxide (37 mg,0.385 mmol) DavePhos (10 mg, 0.025 mmol), Pd₂(dba)₃ (18 mg, 0.020 mmol),and 2-bromo-4-methylpyrimidine (21.4 mg, 0.124 mmol) were added and thereaction left to stir at 100° C. for 3.5 h. The reaction mixture wasallowed to cool to rt and then filtered through celite and the celitewashed with ethyl acetate. The combined filtrates were concentrated invacuo to give a crude orange/brown gum. This gum was purified by MDAP(Formic) to give an off-white solid. This solid was eluted through a NH₂SPE (5 g) with MeOH, the eluent was concentrated to give the product (6mg, 0.015 mmol, 12.26%) as a yellow solid.

LCMS (2 min Formic): Rt=0.80 min, [MH]⁺=395.

Example 172:rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

To a reaction vessel 4-bromo-N-methylbenzamide (53.1 mg, 0.248 mmol),rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 152, 37.5 mg, 0.124mmol), sodium tert-butoxide (35.8 mg, 0.372 mmol), in 1,4-Dioxane (5 mL)were added. The solution was treated with Pd₂(dba)₃ (17.03 mg, 0.019mmol) and DavePhos (9.76 mg, 0.025 mmol) and left to stir at 100° C. for2 h under N₂. The reaction mixture was allowed to cool to rt and thenfiltered through celite and the celite washed with ethyl acetate. Thecombined filtrates were concentrated in vacuo to a crude orange/browngum. This gum was purified by MDAP (Formic) to give a solid. This solidwas eluted through a NH₂ SPE (5 g) with MeOH, the eluent wasconcentrated to give the product (17 mg, 0.039 mmol, 31.5%) as anoff-white solid. LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=436.

Example 173:rac-5-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

To a microwave vial 5-chloropyrazine-2-carbonitrile (34.6 mg, 0.248mmol),rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for preparation see Intermediate 152, 37.5 mg, 0.124 mmol), and DIPEA(0.065 mL, 0.372 mmol) were added and the reaction irradiated in amicrowave at 200° C. for 30 min. The reaction was purified directly byMDAP (Formic) to give a pale yellow solid. This solid was eluted througha NH₂ SPE (5 g) with MeOH, the eluent was concentrated to give theproduct (22 mg, 0.054 mmol, 43.8%) as an orange/red solid. LCMS (2 minFormic): Rt=0.89 min, [MH]⁺=406.

Example 174:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel 2-chloro-5-methylpyrazine (31.9 mg, 0.248 mmol),rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for preparation see Intermediate 152, 37.5 mg, 0.124 mmol), sodiumtert-butoxide (35.8 mg, 0.372 mmol), in 1,4-dioxane (5 mL) were added.The solution was treated with Pd₂(dba)₃ (17.03 mg, 0.019 mmol) andDavePhos (9.76 mg, 0.025 mmol) and left to stir at 100° C. for 72 hunder N₂. The reaction mixture was allowed to cool to rt and thenfiltered through celite and the celite washed with ethyl acetate. Thecombined filtrates were concentrated in vacuo to give a crudeorange/brown gum. This gum was purified by MDAP (Formic). This wasdissolved in methanol (15 mL) and eluted through a pre-equilibrated —NH2column (5 g) and the column washed with methanol (2×15 mL). Theresulting solution was evaporated to give 28 mg of the product as an offwhite solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=395.

Example 175:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel 2-bromo-4-methylpyrimidine (120 mg, 0.695 mmol),rac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for preparation see Intermediate 154, 110 mg, 0.348 mmol), sodiumtert-butoxide (100 mg, 1.043 mmol), in 1,4-dioxane (5 mL) were added.The solution was treated with Pd₂(dba)₃ (47.7 mg, 0.052 mmol) andDavePhos (27.4 mg, 0.070 mmol) and left to stir at 100° C. for 2 h underN₂. The reaction was treated with further sodium tert-butoxide (50 mg,0.520 mmol), Pd₂(dba)₃ (25 mg, 0.027 mmol), 2-bromo-4-methylpyrimidine(45.7 mg, 0.264 mmol) and DavePhos (19.56 mg, 0.050 mmol) were added andthe reaction was left to stir for a further 67 h at 100° C. under N₂.The reaction was treated with further sodium tert-butoxide (45 mg, 0.468mmol) DavePhos (19 mg, 0.048 mmol) and Pd₂(dba)₃ (30 mg, 0.033 mmol) andthe reaction left to stir at 100° C. for 4 h under N₂. The reactionmixture was allowed to cool to rt and was filtered through celite andthe celite washed with ethyl acetate (3×15 mL). The combined filtrateswere washed with brine (45 mL) the organic phase was dried through ahydrophobic frit and concentrated in vacuo to give a crude brown gum.This was purified by column chromatography on silica gel eluting with0-100% ethyl acetate/cyclohexane to give a yellow solid. This solid waspurified by MDAP (Formic) but the product was still of insufficientpurity so was again purified by MDAP (HpH). The solvent was evaporatedin vacuo to give the product (9 mg, 0.022 mmol, 6.34%) as a colourlessgum.

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=409.

Example 176:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

The 2-bromo-6-methoxypyridine (0.200 mL, 1.593 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 260 mg, 0.796 mmol), Pd₂(dba)₃(109 mg, 0.119 mmol), sodium tert-butoxide (230 mg, 2.389 mmol) andDavePhos (31.3 mg, 0.080 mmol) were suspended in 1,4-dioxane (10 mL) andallowed to stir at 100° C. for 16 h. The reaction was concentrated andpartitioned between water and EtOAc, the organic layer was washed withbrine, dried using a hydrophobic frit and concentrated to a gum. Thisgum was purified using a 25 g silica column, elute: 0-50%EtOAc:cyclohexane one major peak was eluted, the appropriate fractionswere summed and concentrated to give the product (242 mg, 0.558 mmol,70.1%) as a yellow solid.

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=434.

Example 177:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,formic acid salt

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 117 mg, 0.358 mmol),2-chloropyrimidine (82 mg, 0.717 mmol) and DIPEA (0.188 mL, 1.075 mmol)were taken up in N-methyl-2-pyrrolidone (NMP) (5 mL) placed in amicrowaveable vial and irradiated in a microwave at 150° C. for 1 h. Thereaction was irradiated for a further 1 h at 200° C. and then 2 h at200° C. The reaction was partitioned between water and EtOAc, theorganic layer was washed with 10% LiCl(aq), dried using a hydrophobicfrit and concentrated to a orange oil. This oil was purified using aMDAP (Formic). The appropriate fractions were summed and concentrated togive the product (21 mg, 0.047 mmol, 13.0%) as an orange solid. LCMS (2min formic): Rt=0.91 min, [MH]⁺=405.

Example 178:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 200 mg, 0.613 mmol), Pd₂(dba)₃(84 mg, 0.092 mmol), sodium tert-butoxide (177 mg, 1.838 mmol), DavePhos(24.11 mg, 0.061 mmol) and 4-bromo-N-methylbenzamide (262 mg, 1.225mmol) were suspended in 1,4 dioxane (10 mL) and allowed to stir at 100°C. for 16 h. The reaction was allowed to cool to rt and was partionedbetween water and EtOAc, the organic phase was washed with brine, driedusing a hydrophobic frit and concentrated to a gum. This gum waspurified using column chromatography on silica gel eluting with 0-100%EtOAc:cyclohexane, and then 0-10% MeOH:DCM, to give a crude solid whichwas further purified by MDAP (Formic) to give a solid which was elutedthrough a NH₂ SPE (1 g) with MeOH, the eluent was concentrated and driedto give the product (45 mg, 0.098 mmol, 15.98%) as a white solid. LCMS(2 min Formic): Rt=0.92 min, [M−H]⁻=458.

Example 179:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The 2-chloro-5-methylpyrazine (0.053 mL, 0.613 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 100 mg, 0.306 mmol), Pd₂(dba)₃(42.1 mg, 0.046 mmol), sodium tert-butoxide (88 mg, 0.919 mmol) andDavePhos (12.06 mg, 0.031 mmol) were suspended in 1,4-dioxane (10 mL)and allowed to stir at 100° C. for 3 h. The reaction was allowed to cooland was partitioned between water and EtOAc, the organic layer waswashed with brine, dried using a hydrophobic frit and concentrated to agum. This gum was purified by column chromatography on silica geleluting with 0-50% EtOAc:cyclohexane and then 0-10% MeOH:DCM, to give acrude gum. This gum was further purified using a MDAP (Formic) to give awhite solid, this solid was eluted through a NH₂ SPE (2 g) with MeOH theeluent was concentrated and dried to give the product (46 mg, 0.110mmol, 35.9%) as an off-white solid. LCMS (2 min Formic): Rt=0.93 min,[MH]⁺=419.

Example 180:rac-5-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

The 5-chloropyrazine-2-carbonitrile (0.034 mL, 0.368 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 78, 60 mg, 0.184mmol), DIPEA (0.096 mL, 0.551 mmol) and N-methyl-2-pyrrolidone (NMP) (2mL) were irradiated in a microwave at 200° C. for 1 h. The reaction waspurified directly using a MDAP (Formic) to give a brown solid. Thissolid was eluted through a NH₂ SPE (5 g) using MeOH, the eluent wasconcentrated and dried to give the product (34 mg, 0.079 mmol, 43.1%) asa brown solid. LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=430.

Example 181:rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

The 6-fluoronicotinonitrile (0.030 mL, 0.368 mmol),rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 60 mg, 0.184 mmol),6-fluoronicotinonitrile (0.030 mL, 0.368 mmol), DIPEA (0.096 mL, 0.551mmol) and N-methyl-2-pyrrolidone (NMP) (2 mL) were irradiated in amicrowave at 200° C. for 30 min. The reaction was purified directlyusing a MDAP (Formic) to give a brown solid. This solid was elutedthrough a NH₂ SPE (5 g) using MeOH, the eluent was concentrated anddried to give the product (43 mg, 0.100 mmol, 54.6%) as a yellow solid.

LCMS (2 min Formic): Rt=1.01 min, [MH]⁺=429.

Example 182:rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 78, 200 mg, 0.613 mmol), Pd₂(dba)₃(84 mg, 0.092 mmol), sodium tert-butoxide (177 mg, 1.838 mmol), DavePhos(24.11 mg, 0.061 mmol) and 2-bromo-4-methylpyrimidine (212 mg, 1.225mmol) were suspended in 1,4 dioxane (10 mL) and allowed to stir at 100°C. for 16 h. The reaction was treated with further Pd₂(dba)₃ (84 mg,0.092 mmol) and was allowed to stir at 100° C. for a further 24 h. Thereaction was transferred to microwave vial and was irradiated in amicrowave at 140° C. for 2 h. The reaction was allowed to cool to rt andwas partioned between water and EtOAc, the organic phase was washed withbrine, dried using a hydrophobic frit and concentrated to a gum. Thisgum was purified by column chromatography on silica gel eluting with0-10% MeOH:DCM to give a crude oil. This oil was purified using a MDAP(Formic) and the appropriate fractions were concentrated to give an oilwhich was eluted through a NH₂ SPE (1 g) with MeOH, washing with furtherMeOH. The eluent was concentrated to give the product (10 mg, 0.024mmol, 3.90%) as a yellow oil.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=419.

Example 183:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone,hydrochloride

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 157, 23 mg, 0.047 mmol) in1,4-dioxane (1 mL) was treated with 4M HCl in dioxane (1 mL, 4.00 mmol)and stirred in a closed vessel at rt for 1 h. The solvent was evaporatedin vacuo to give the title compound (18 mg, 0.042 mmol, 90%). LCMS (2min Formic): Rt=0.58 min, [MH]⁺=394.

Example 184:rac-1-((2S,3R,4R)-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone,2 hydrochloride

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(fora preparation see Intermediate 158, 67 mg, 0.135 mmol) in1,4-dioxane (1 mL) was treated with 4M HCl in dioxane (1 mL, 4.00 mmol)and stirred in a closed vessel at rt for 1 h. The solvent was evaporatedin vacuo to give the title compound (60 mg, 0.128 mmol, 95%). LCMS (2min Formic): Rt=0.59 min, [MH]⁺=397.

Example 185:rac-1-((2S,3R,4R)-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-6-(piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone,2 hydrochloride

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 159, 55 mg, 0.112 mmol) in1,4-dioxane (1 mL) was treated with 4 M HCl in 1,4-dioxane (1 mL, 4.00mmol) and stirred in a closed vessel at rt for 1 h. The solvent wasevaporated in vacuo to give the title compound (50 mg, 0.107 mmol, 96%).LCMS (2 min Formic): Rt=0.47 min, [MH]⁺=393.

Example 186:rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

A solution of tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(fora preparation see Intermediate 160, 15 mg, 0.030 mmol) and 4M HCl indioxane (1 mL, 4.00 mmol) in 1,4-dioxane (1 mL) was stirred in a closedvessel at rt for 1 h. The solvent was concentrated in vacuo and thesample was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (HpH).The appropriate fractions were combined and concentrated in vacuo togive the product (6.2 mg, 0.015 mmol, 51.6%).

LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=403.

Example 187:rac-6-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 161, 21 mg, 0.042 mmol) and 4M HClin dioxane (1.042 mL, 4.17 mmol) in 1,4-dioxane (1 mL) was stirred at rtfor 1 h in a closed vessel. The solvent was evaporated in vacuo and thesample was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP(Formic). The appropriate fractions were combined and concentrated invacuo to give the product (6.1 mg, 0.015 mmol, 36.3%).

LCMS (2 min Formic): Rt=0.64 min, [MH]⁺=404.

Example 188:rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

A solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 162, 15 mg, 0.028 mmol) and 4M HClin dioxane (1 mL, 4.00 mmol) in 1,4-dioxane (1 mL) was stirred in aclosed vessel at rt for 1 h. The solvent was evaporated in vacuo and thesample was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (HpH).The appropriate fractions were combined and concentrated in vacuo togive the product (5.3 mg, 0.012 mmol, 43.5%). LCMS (2 min Formic):Rt=0.59 min, [MH]⁺=435.

Example 189a & 189b:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(189a) &1-((2R,3S,4S)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(189b)

rac-1-((2S,3R,4R)-2-Cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 87, 70 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×30 mm ChiralpakAD-H column eluting with 92.5:7.5 (plus 0.2% isopropylamine) at a flowrate of 42.5 mL/min. Peak 1/Enantiomer A fractions were collectedbetween 13 and 15 min, and Peak 2/Enantiomer B fractions were collectedbetween 22.5 and 26 min. Fraction solutions were combined and thenevaporated to dryness to give Enantiomer A (30 mg) and Enantiomer B (30mg) as white solids.

Enantiomer A, Example 189a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 10% ethanol in heptanes (plus 0.2% isopropylamine) at 1mL/min—Rt=8.5 min. >99% ee by UV.

Enantiomer B, Example 189b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 10% ethanol in heptanes (plus 0.2% isopropylamine) at 1mL/min—Rt=11.5 min, >99% ee by UV.

Example 190:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 163, 20 mg, 0.038 mmol), TMSCl(0.029 mL, 0.225 mmol) and sodium iodide (33.8 mg, 0.225 mmol) werestirred in acetonitrile (0.05 mL) and heated at 55° C. for 2 days. Thereaction mixture was filtered though a cotton wool plug and the filtratewas concentrated. The residue was purified using MDAP (Formic).Evaporation of the desired fractions gave the product as a white solid(8 mg). LCMS (2 min Formic): Rt=0.58 min, [MH]⁺=419.

Example 191:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 163, 10 mg, 0.019 mmol) wasdissolved in 4M hydrochloric acid (0.5 mL, 2.0 mmol) in 1,4-dioxane. Thereaction was stirred at rt for 1 h. The solvent and excess HCl wereremoved under reduced pressure to leave the product HCl salt as a yellowsolid. Purification was undertaken using MDAP (Formic). The collectedfractions were evaporated to leave the product as a white solid (5 mg).LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=433.

Example 192:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 164, 10 mg, 0.019 mmol) wasdissolved in 4M hydrochloric acid (0.5 mL, 2.0 mmol) in 1,4-dioxane. Thereaction was stirred at rt for 1 h. The solvent and excess HCl wereremoved under reduced pressure to leave the product HCl salt.Purification was undertaken using MDAP (HpH). The collected fractionswere evaporated to leave the product as a white solid (5 mg).

LCMS (2 min Formic): Rt=0.76 min, [MH]⁺=427.

Example 193:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 165, 10 mg, 0.018 mmol) wasdissolved in 4M hydrochloric acid (0.5 mL, 2.0 mmol) in 1,4-dioxane. Thereaction was stirred at rt for 1 h. The solvent and excess HCl wereremoved under reduced pressure to leave the product HCl salt.Purification was undertaken using MDAP (HpH). The collected fractionswere evaporated to leave the product as a white solid (7 mg).

LCMS (2 min Formic): Rt=0.65 min, [MH]⁺=459.

Example 194:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

rac-tert-Butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 166, 10 mg, 0.019 mmol) wasdissolved in 4M hydrochloric acid (0.5 mL, 2.0 mmol) in 1,4-dioxane. Thereaction was stirred at rt for 1 h. The solvent and excess HCl wereremoved under reduced pressure to leave the crude product. Purificationwas undertaken using MDAP (HpH). The collected fractions were evaporatedto leave the product as a white solid (8 mg).

LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=418.

Example 195:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile,formic acid salt

To a solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 167, 80 mg, 0.152 mmol) in1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (2.00 mL). Theresulting reaction mixture was stirred at rt for 1 hour, whereupon itwas concentrated in vacuo. The crude residue was dissolved in a 1:1DMSO/MeOH mixture and was purified via MDAP (Formic). The appropriatefractions were combined and concentrated in vacuo to give the product asa white solid (11 mg). LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=429.

Example 196:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-(piperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide,formic acid salt

To a solution of rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(for a preparation see Intermediate 168, 29 mg, 0.052 mmol) in1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (2.00 mL). Theresulting reaction mixture was stirred at rt for 1 h, whereupon it wasconcentrated in vacuo. The crude residue was dissolved in a 1:1DMSO/MeOH mixture and was purified via MDAP (Formic). The appropriatefractions were combined and concentrated in vacuo to give the product asan off-white solid (12 mg). LCMS (2 min Formic): Rt=0.65 min, [MH]⁺=461.

Example 197:4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

A microwave vial was charged with1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 211, 125 mg, 72% purity, 0.297 mmol,˜25% ee) in 1,4-dioxane (2 mL) followed by 4-bromobenzonitrile (108 mg,0.593 mmol), then sodium tert-butoxide (57 mg, 0.593 mmol), DavePhos (24mg, 0.061 mmol), and Pd₂(dba)₃ (54 mg, 0.059 mmol). The reaction mixturewas heated to 100° C. for 45 min using a microwave reactor, then dilutedwith EtOAc and filtered through a pad of celite. The celite pad waswashed with EtOAc (10 mL) and the filtrate concentrated under reducedpressure. The residue was purified by MDAP (Formic). The desiredfractions were combined and evaporated in vacuo and the residuedissolved in methanol then passed through an amino-propyl SPE columnwhich was washed with further methanol. The methanol washes werecombined then concentrated in vacuo to afford the desired product as awhite solid (13 mg, ˜25% ee).

LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=405.

Example 198:1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

A microwave vial was charged with1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 211, 125 mg, 72% purity, 0.297 mmol,˜25% ee) in 1,4-dioxane (2 mL) followed by 2-bromo-4-methylpyrimidine(103 mg, 0.593 mmol), then sodium tert-butoxide (57 mg, 0.593 mmol),DavePhos (24 mg, 0.061 mmol), and Pd₂(dba)₃ (54 mg, 0.059 mmol). Thereaction mixture was heated to 100° C. for 45 min using a microwavereactor, then diluted with EtOAc and filtered through a pad of celite.The celite pad was washed with EtOAc (10 mL) and the filtrateconcentrated under reduced pressure. The residue was purified by MDAP(Formic). The desired fractions were combined and evaporated in vacuoand the residue dissolved in methanol then passed through anamino-propyl SPE column which was washed with further methanol. Themethanol washes were combined then concentrated in vacuo to afford thedesired product as a white solid (17 mg, ˜25% ee).

LCMS (2 min Formic): Rt=0.71 min, [MH]⁺=396.

Example 199:rac-4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

A microwave vial was charged with1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 211, 125 mg, 72% purity, 0.297 mmol,˜25% ee) in 1,4-dioxane (2 mL) followed by 4-bromo-N-methylbenzamide(127 mg, 0.593 mmol), then sodium tert-butoxide (57 mg, 0.593 mmol),DavePhos (24 mg, 0.061 mmol), and Pd₂(dba)₃ (54 mg, 0.059 mmol). Thereaction mixture was heated to 100° C. for 45 min using a microwavereactor, then diluted with EtOAc and filtered through a pad of celite.The celite pad was washed with EtOAc (10 mL) and the filtrateconcentrated under reduced pressure. The residue was purified by MDAP(Formic). The desired fractions were combined and evaporated in vacuoand the residue dissolved in methanol then passed through anamino-propyl SPE column which was washed with further methanol. Themethanol washes were combined then concentrated in vacuo to afford thedesired product as a white solid (8 mg, ˜25% ee).

LCMS (2 min Formic): Rt=0.76 min, [MH]⁺=437.

Example 200:1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

A microwave vial was charged with1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 211, 125 mg, 72% purity, 0.297 mmol,˜25% ee) in 1,4-dioxane (2 mL) followed by 2-chloro-5-methylpyrazine (76mg, 0.593 mmol), then sodium tert-butoxide (57 mg, 0.593 mmol), DavePhos(24 mg, 0.061 mmol), and Pd₂(dba)₃ (54 mg, 0.059 mmol). The reactionmixture was heated to 100° C. for 45 min using a microwave.reactor, thendiluted with EtOAc and filtered through a pad of celite. The celite padwas washed with EtOAc (10 mL) and the filtrate concentrated underreduced pressure. The residue was purified by MDAP (Formic). The desiredfractions were combined and evaporated in vacuo and the residuedissolved in methanol then passed through an amino-propyl SPE columnwhich was washed with further methanol. The methanol washes werecombined then concentrated in vacuo to afford the desired product as awhite solid (9 mg, ˜25% ee).

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=396.

Example 201:rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 73, 40 mg, 0.126 mmol) inN-methyl-2-pyrrolidone (1.6 mL) was added N,N-diisopropylethylamine(0.066 mL, 0.378 mmol) and 2-bromo-4-methylpyrimidine (43.6 mg, 0.252mmol). The reaction mixture was heated under microwave conditions, usinginitial high absorption setting, to 200° C. for 30 min.N-Methyl-2-pyrrolidone (0.3 mL) was added and the solution was purifiedby MDAP (HpH). The solvent was blown down under a stream of nitrogen togive a brown gum. The sample was dissolved in DMSO (1 mL) and purifiedby MDAP (Formic). The solvent was blown down under a stream of nitrogento give the required product (9 mg) as an off-white gum. LCMS (2 minHpH): Rt=0.90 min, [MH]⁺=410.

Example 202:rac-6-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

To a solution ofrac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(fora preparation see Intermediate 73, 40 mg, 0.126 mmol) inN-methyl-2-pyrrolidone (1.6 mL) was added N,N-diisopropylethylamine(0.066 mL, 0.378 mmol) and 6-fluoronicotinonitrile (30.8 mg, 0.252mmol). The reaction mixture was heated under microwave conditions, usinginitial high absorption setting, to 200° C. for 30 min.N-Methyl-2-pyrrolidone (0.3 ml) was added and the solution purified byMDAP (HpH). The solvent was blown down under a stream of nitrogen togive a dark brown gum. The sample was loaded in methanol and purified byaminopropyl SPE (1 g) eluted using methanol. The appropriate fractionswere combined and blown down under a stream of nitrogen to give therequired product (23 mg) as a yellow gum.

LCMS (2 min HpH): Rt=0.94 min, [MH]⁺=420.

Example 203:rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 73, 50 mg, 0.158 mmol) in1,4-dioxane (1.5 ml) was added tris(dibenzylideneacetone)dipalladium(0)(28.8 mg, 0.032 mmol), Davephos (12.40 mg, 0.032 mmol), sodiumtert-butoxide (30.3 mg, 0.315 mmol) and 2-chloro-5-methylpyrazine (40.5mg, 0.315 mmol). The reaction mixture was heated under microwaveconditions, using initial normal absorption setting, to 120° C. for 30min. The sample was diluted with ethyl acetate (5 mL) and loaded onto acelite cartridge (2.5 g). The cartridge was washed with further ethylacetate (2×10 mL), and the combined fractions dried under a stream ofnitrogen. The sample was dissolved in DMSO (2×1 mL) and purified by MDAP(HpH). The solvent was blown down under a stream of nitrogen to give therequired product (14 mg) as a yellow gum. LCMS (2 min HpH): Rt=0.87 min,[MH]⁺=410.

Example 204:rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 73, 50 mg, 0.158 mmol) in1,4-dioxane (1.5 mL) was added 2-bromo-6-methylpyridine (0.036 mL, 0.315mmol), Pd₂(dba)₃ (28.8 mg, 0.032 mmol), DavePhos (12.40 mg, 0.032 mmol)and sodium tert-butoxide (30.3 mg, 0.315 mmol). The reaction mixture wasdegassed for 5 min, and then heated under microwave conditions, usinginitial normal absorption setting, to 120° C. for 30 min. The sample wasdiluted with ethyl acetate (5 mL) and loaded onto a celite cartridge(2.5 g). The cartridge was washed with further ethyl acetate (2×10 mL),and the combined fractions dried under a stream of nitrogen. The residuewas dissolved in DMSO (2×1 mL) and purified by MDAP (HpH). The first ofthe two MDAP runs sent the product to the waste bottle. The waste wastherefore evaporated under reduced pressure to give a yellow gum. Thissample was dissolved in DMSO (1 mL) and re-purified by MDAP (HpH). Thesolvent was blown down under a stream of nitrogen to give a yellow gum(14 mg). The second of the two MDAP runs collected correctly, thesolvent was blown down under a stream of nitrogen to give a yellow gum(13 mg). Both samples were combined and dissolved in DMSO (0.5 mL) andpurified by MDAP (Formic). The product was sent to the waste bottle. Thewaste was therefore evaporated under reduced pressure to give a yellowgum. This residue was dissolved in DMSO (1 mL) and purified by MDAP(Formic). The solvent was blown down under a stream of nitrogen to givethe required product (14 mg) as a colourless gum. LCMS (2 min HpH):Rt=1.03 min, [MH]⁺=409.

Example 205:rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

To a solution ofrac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 73, 50 mg, 0.158 mmol) in1,4-dioxane (1.5 mL) was added 4-bromobenzonitrile (57.3 mg, 0.315mmol), Pd₂(dba)₃ (28.8 mg, 0.032 mmol), DavePhos (12.40 mg, 0.032 mmol)and sodium tert-butoxide (30.3 mg, 0.315 mmol). The reaction mixture wasdegassed for 5 min, and then heated under microwave conditions, usinginitial normal absorption setting, to 120° C. for 30 min. The sample wasdiluted with ethyl acetate (5 mL) and loaded onto a celite cartridge(2.5 g). The cartridge was washed with further ethyl acetate (2×10 mL),and the combined fractions dried under a stream of nitrogen. The residuewas dissolved in DMSO (2×1 mL) and purified by MDAP (HpH). Only one ofthe two runs collected correctly. The solvent from this run was blowndown under a stream of nitrogen to give the required product (11 mg) asa yellow gum. LCMS (2 min HpH): Rt=1.03 min, [MH]⁺=419.

Example 206:rac-1-((2S,3R,4R)-2-ethyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2S,3R,4R)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 73, 100 mg, 0.315 mmol) in1,4-dioxane (3 mL) was added 2-bromo-6-methoxypyridine (0.077 ml, 0.630mmol), Pd₂(dba)₃ (57.7 mg, 0.063 mmol), DavePhos (24.80 mg, 0.063 mmol)and sodium tert-butoxide (60.6 mg, 0.630 mmol). The reaction mixture wasdegassed for 5 min, and then heated under microwave conditions, usinginitial normal absorption setting, to 120° C. for 30 min. The sample wasdiluted with ethyl acetate (10 mL) and loaded onto a celite cartridge(2.5 g). The cartridge was washed with further ethyl acetate (2×20 mL),and the combined fractions dried under a stream of nitrogen. The residuewas dissolved in DMSO (3×1 mL) and purified by MDAP (HpH). The solventwas blown down under a stream of nitrogen to give the required product(83 mg) as an off-white gum.

LCMS (2 min HpH): Rt=1.08 min, [MH]⁺=425.

Example 207:rac-1-((2S,3R,4R)-2-ethyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2S,3R,4i)-4-amino-2-ethyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 73, 50 mg, 0.158 mmol) in1,4-dioxane (1.5 mL) was added 2-bromo-5-fluoropyridine (55.4 mg, 0.315mmol), Pd₂(dba)₃ (28.8 mg, 0.032 mmol), DavePhos (12.40 mg, 0.032 mmol)and sodium tert-butoxide (30.3 mg, 0.315 mmol). The reaction mixture wasdegassed for 5 min, and then heated under microwave conditions, usinginitial normal absorption setting, to 120° C. for 30 min. The sample wasdiluted with ethyl acetate (5 mL) and loaded onto a celite cartridge(2.5 g). The cartridge was washed with further ethyl acetate (2×10 mL),and the combined fractions dried under a stream of nitrogen. The residuewas dissolved in DMSO (2×1 mL) and purified by MDAP (HpH). The solventwas blown down under a stream of nitrogen to give an off-white gum (12mg). The sample was dissolved in DMSO (0.5 mL) and purified by MDAP(Formic). The solvent was blown down under a stream of nitrogen to givethe required product (11 mg) as an off-white gum. LCMS (2 min HpH):Rt=1.00 min, [MH]⁺=413.

Example 208:rac-4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

A solution ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 60 mg, 0.182 mmol), DavePhos (7.17mg, 0.018 mmol), Pd₂(dba)₃ (8.34 mg, 9.11 μmol), sodium tert-butoxide(35.0 mg, 0.364 mmol) and 4-bromo-N-methylbenzamide (46.8 mg, 0.219mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C. for 6h. The reaction mixture was allowed to cool to rt, filtered throughcelite and rinsed with ethyl acetate. The solvent was evaporated invacuo to give 120 mg crude as an orange gum. The crude was dissolved in1:1 MeOH:DMSO (2×1 mL) and purified by MDAP (HpH). The appropriatefractions were combined and concentrated in vacuo to give the product(20 mg, 0.043 mmol, 23.74%). LCMS (2 min Formic): Rt=0.84 min,[MH]⁺=463.

Example 209:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone,formic acid salt

A solution ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 83, 60 mg, 0.182 mmol), DavePhos(7.17 mg, 0.018 mmol), 2-bromo-4-methylpyrimidine (37.8 mg, 0.219 mmol),sodium tert-butoxide (35.0 mg, 0.364 mmol) and Pd₂(dba)₃ (8.34 mg, 9.11μmol) in 1,4-dioxane (2 mL) was stirred under nitrogen at 90° C. for 72h. All reactants were added again to the reaction. The reaction mixturewas stirred under nitrogen at 90° C. for 7 h. The reaction mixture wasallowed to cool to rt, filtered through celite and rinsed with ethylacetate. The solvent was evaporated in vacuo then a solution of DavePhos(7.17 mg, 0.018 mmol), 2-bromo-4-methylpyrimidine (37.8 mg, 0.219 mmol),sodium tert-butoxide (35.0 mg, 0.364 mmol) and Pd₂(dba)₃ (8.34 mg, 9.11μmol) in 1,4-dioxane (2 mL) was added. The reaction mixture was stirredunder nitrogen at 90° C. for 16 h. The reaction mixture was allowed tocool to rt, filtered through celite and rinsed with ethyl acetate. Thesolvent was evaporated in vacuo then the sample was dissolved in 1:1MeOH:DMSO (3×1 mL) and purified by MDAP (3× Formic). Only the 3^(rd) runcollected material. The appropriate fraction was concentrated in vacuoto give the title compound (10 mg, 0.021 mmol, 11.74%). LCMS (2 minFormic): Rt=0.81 min, [MH]⁺=422.

Example 210:rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-hydroxypyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution ofrac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 171, 120 mg, 0.275 mmol), sodiumiodide (247 mg, 1.649 mmol) and TMSCl (0.211 mL, 1.649 mmol) inacetonitrile (2 mL) was stirred under nitrogen at 55° C. for 16 h. TMSCl(0.211 mL, 1.649 mmol) was added and the reaction was stirred undernitrogen at 55° C. for 4 h. The temperature was raised to 75° C. andleft to stir under nitrogen for 16 h. The reaction mixture wasconcentrated in vacuo then dissolved in DCM (10 mL). The organicsolution was washed with 0.5M NaOH (2×10 mL), filtered through ahydrophobic frit then concentrated in vacuo to give 40 mg crude. Thecrude was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP(Formic). The appropriate fraction was concentrated in vacuo to give thetitle compound (8 mg, 0.019 mmol, 7%).

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=423.

Example 211:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 83, 100 mg, 0.304 mmol), DavePhos(11.95 mg, 0.030 mmol), 2-chloro-5-methylpyrazine (46.8 mg, 0.364 mmol),Pd₂(dba)₃ (13.90 mg, 0.015 mmol) and sodium tert-butoxide (58.3 mg,0.607 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C.for 20 h. The reaction mixture was allowed to cool to rt, filteredthrough celite and rinsed with ethyl acetate. The solvent was evaporatedin vacuo then the sample was dissolved in 1:1 MeOH:DMSO (1 mL) andpurified by MDAP (HpH). The appropriate fractions were combined andconcentrated in vacuo to give the title compound (36 mg, 0.085 mmol,28%).

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=422.

Example 212:rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-morpholino-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

A solution ofrac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 83, 128 mg, 0.389 mmol), DavePhos(15.29 mg, 0.039 mmol), 6-bromonicotinonitrile (85 mg, 0.466 mmol),Pd₂(dba)₃ (17.79 mg, 0.019 mmol) and sodium tert-butoxide (74.7 mg,0.777 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90° C.for 7 h. The reaction mixture was allowed to cool to rt, filteredthrough celite and rinsed with ethyl acetate. The solvent was evaporatedin vacuo then the sample was dissolved in 1:1 MeOH:DMSO (1 mL) andpurified by MDAP (HpH). The appropriate fractions were combined andconcentrated in vacuo to give the title compound (61 mg, 0.141 mmol,36%).

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=432.

Example 213:5-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

A solution of tert-butyl4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 213, 69 mg, 0.151 mmol) in NMP (1.5mL) was treated with 5-chloropyrazine-2-carbonitrile (22 mg, 0.158 mmol)and DIPEA (0.079 mL, 0.453 mmol) then the mixture was heated at 200° C.for 30 min using a microwave reactor. The residue was purified by MDAP(Formic). The desired fractions were combined and evaporated in vacuo toafford the desired product as a white solid (17 mg).

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=407.

Example 214:4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

tert-Butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 214, 22 mg, 0.044 mmol) wasdissolved in DCM (2 mL), then TFA added (1 mL). The reaction mixture wasstirred for 2 h then concentrated under a stream of nitrogen. Theresulting residue was dissolved in methanol then passed through anamino-propyl SPE column which was washed with further methanol. Themethanol washes were combined then concentrated under a stream ofnitrogen to give the desired product as a pale brown gum (17 mg). LCMS(2 min Formic): Rt=0.67 min, [MH]⁺=404.

Example 215:1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

tert-Butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 215, 14 mg, 0.028 mmol) wasdissolved in DCM (2 mL), then TFA added (1 mL). The reaction mixture wasstirred for 2 h then concentrated under a stream of nitrogen. Theresulting residue was dissolved in methanol then passed through anamino-propyl SPE column which was washed with further methanol. Themethanol washes were combined then concentrated under a stream ofnitrogen to give the desired product as a pale brown gum (12 mg).

LCMS (2 min Formic): Rt=0.53 min, [MH]⁺=395.

Example 216:4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

tert-Butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 216, 13 mg, 0.024 mmol) wasdissolved in DCM (2 mL), then TFA added (1 mL). The reaction mixture wasstirred for 2 h then concentrated under a stream of nitrogen. Theresulting residue was dissolved in methanol then passed through anamino-propyl SPE column which was washed with further methanol. Themethanol washes were combined then concentrated under a stream ofnitrogen to give the desired product as a pale brown gum (8 mg).

LCMS (2 min Formic): Rt=0.56 min, [MH]⁺=436.

Example 217:1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

tert-Butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 217, 10 mg, 0.020 mmol) wasdissolved in DCM (2 mL), then TFA added (1 mL). The reaction mixture wasstirred for 2 h then concentrated under a stream of nitrogen. Theresulting residue was dissolved in methanol then passed through anamino-propyl SPE column which was washed with further methanol. Themethanol washes were combined then concentrated under a stream ofnitrogen to give the desired product as a pale brown gum (9 mg).

LCMS (2 min Formic): Rt=0.56 min, [MH]⁺=395.

Example 218:rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-6-(piperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a flask containing rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 173, 21.6 mg, 0.042 mmol) indichloromethane (DCM) (1 mL) was added TFA (250 μL, 3.24 mmol) and thereaction was stirred for 1 h. The reaction mixture was concentrated invacuo to afford a brown oil. This was dissolved in methanol and loadedonto an SCX cartridge (5 g). It was eluted with methanol (3 CVs) and theproduct was eluted as its free base with 2M ammonia in methanol. Thefiltrate from the ammonia fractions was concentrated in vacuo to yield acolourless gum (16.6 mg, 0.041 mmol, 96%). LCMS (2 min Formic): Rt=0.60min, [MH]⁺=409.

Example 219:rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

To a flask containing rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 174, 24 mg, 0.046 mmol) indichloromethane (DCM) (1 mL) was added TFA (250 μL, 3.24 mmol) and thereaction was stirred for 1 h. The reaction mixture was concentrated invacuo to afford a brown oil. This was dissolved in methanol and loadedonto an SCX cartridge (5 g). It was eluted with methanol (3 CVs) and theproduct eluted as its free base with 2M ammonia in methanol. Thefiltrate from the ammonia fractions was concentrated in vacuo to yield acolourless gum (18.9 mg, 0.045 mmol, 98%). LCMS (2 min Formic): Rt=0.72min, [MH]⁺=418.

Example 220:rac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

To a flask containing rac-tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 175, 13 mg, 0.024 mmol) indichloromethane (DCM) (1 mL) was added TFA (250 μL, 3.24 mmol) and thereaction was stirred for 1 h. The reaction mixture was concentrated invacuo to afford a brown oil. This was dissolved in methanol and loadedonto an SCX cartridge (5 g). It was eluted with methanol (3 CVs) and theproduct eluted as its free base with 2M ammonia in methanol. Thefiltrate from the ammonia fractions was concentrated in vacuo to yield acolourless gum (10.1 mg, 0.022 mmol, 95%).

LCMS (2 min Formic): Rt=0.61 min, [MH]⁺=450.

Example 221:rac-5-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

To a flask containing rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 176, 26.6 mg, 0.051 mmol) indichloromethane (DCM) (1 mL) was added TFA (250 μL, 3.24 mmol) and thereaction was stirred for 1 h. The reaction mixture was concentrated invacuo to afford a brown oil. This was dissolved in methanol and loadedonto an SCX cartridge (5 g). It was eluted with methanol (3 CVs) andproduct eluted as free base with 2M ammonia in methanol. The filtratefrom the ammonia fractions was concentrated in vacuo to yield a yellowgum, which was still impure. The crude product was therefore furtherpurified. It was taken up in DCM and added to a silica cartridge (10 g).This was purified by flash chromatography eluting with 0-10% 2M NH₃ inMeOH/DCM. The appropriate fractions were collected and concentrated invacuo to afford the desired product as a yellow solid (15.6 mg, 0.037mmol, 72.6%). LCMS (2 min Formic): Rt=0.63 min, [MH]⁺=420.

Example 222:rac-6-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

To a flask containing rac-tert-butyl4-((2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 177, 16.6 mg, 0.032 mmol) indichloromethane (DCM) (1 mL) was added TFA (250 μL, 3.24 mmol) and thereaction was stirred for 1 h. The reaction mixture was concentrated invacuo to afford a brown oil. This was dissolved in methanol and loadedonto an SCX cartridge (5 g). It was eluted with methanol (3 CVs) and theproduct eluted as its free base with 2M ammonia in methanol. Thefiltrate from the ammonia fractions was concentrated in vacuo to yield acolourless gum (13.3 mg, 0.032 mmol, 99%). LCMS (2 min Formic): Rt=0.66min, [MH]⁺=419.

Example 223:4-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

To a stirring solution of (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 180, 22 mg, 0.018 mmol) indichloromethane (DCM) (1 mL) was added trifluoroacetic acid (0.140 mL,1.821 mmol). The mixture was stirred at rt for 30 min. The solution wasconcentrated in vacuo. The sample was dissolved in 1:1 MeOH/DMSO (1 mL)and purified by MDAP (HpH). The solvent was evaporated in vacuo to givethe required product (4.2 mg). This was a mixture of diatereoisomers.LCMS (2 min formic): Rt=0.78 min, [MH]⁺=444.

Example 224:4-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((R)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

To a stirring solution of (R)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 183, 9.1 mg, 0.017 mmol) indichloromethane (DCM) (0.5 mL) under nitrogen was added trifluoroaceticacid (0.129 mL, 1.674 mmol). The mixture was stirred at rt for ˜30 min.The reaction mixture was concentrated in vacuo. The sample was dissolvedin 1:1 MeOH/DMSO (1 mL) and purified by MDAP (HpH). The solvent wasevaporated in vacuo to give the required product (5.2 mg). This was amixture of diastereoisomers.

LCMS (2 min formic): Rt=0.78 min, [MH]⁺=444.

Example 225:1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-((S)-3-methylpiperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

(S)-tert-Butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 222, 68 mg, 0.124 mmol) wasdissolved, in a dried flask, in acetonitrile (0.5 mL). To this was addedTMSCl (0.095 mL, 0.742 mmol) and sodium iodide (111 mg, 0.742 mmol). Themixture was heated to 55° C. under nitrogen for ˜2 h. The mixture wasdiluted with more acetonitrile, filtered through a cotton wool plug, andconcentrated in vacuo. The samples were dissolved in MeOH:DMSO (1:1, 1mL) and purified by MDAP (HpH). The solvent was evaporated in vacuo togive the required product (21.5 mg, 38.7%). LCMS (2 min HpH): Rt=0.99min, [MH]⁺=450.

Example 226:1-((2S,3R,4R)-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-6-((S)-3-methylpiperazin-1-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a stirring solution of (S)-tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 221, 33.7 mg, 0.063 mmol) indichloromethane (DCM) (1.5 mL) was added trifluoroacetic acid (0.483 mL,6.27 mmol). The mixture was stirred at rt for ˜1 h. The mixture wasdiluted with dichloromethane (DCM) and evaporated in vacuo. The residuewas dissolved in methanol and loaded onto a 2 g SCX SPE cartridge whichhad been primed with methanol. The column was eluted with 4 CVs ofmethanol, and the product was then eluted with 6 CVs 2M NH₃ in methanol.The appropriate fractions were collected and concentrated in vacuo toafford the product (9.1 mg). This sample was dissolved in MeOH:DMSO(1:1, 1 mL) and purified by MDAP (HpH). The solvent was evaporated invacuo to give the required product (3.7 mg, 13.5%).

LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=438.

Example 227:1-((rac-2S,3R,4R)-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a stirring solution of (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 184, 5.7 mg, 10.66 μmol) indichloromethane (DCM) (1 mL) under nitrogen was added trifluoroaceticacid (0.25 mL, 3.24 mmol). The mixture was stirred at rt for 45 min. Thereaction was allowed to stir for a further 15 min at rt. A further 100μL of trifluoroacetic acid was added, and the mixture was allowed tostir at rt for a further 20 min. The reaction mixture was concentratedin vacuo and the residue was dissolved in methanol. This solution wasloaded onto a 1 g SCX SPE cartridge, which had been pre-equilibratedwith methanol. The column was eluted with 3 CVs of methanol, and thenthe sample was eluted with 3 CVs of 2M NH₃ in methanol. The appropriatefraction was concentrated in vacuo to give the product (2.4 mg, 5.52μmol, 51.8%). This was a mixture of diastereoisomers. LCMS (2 minFormic): Rt=0.65 min, [MH]⁺=436.

Example 228:4-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide

To a stirring solution of (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(methylcarbamoyl)phenyl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 185, 5.6 mg, 9.73 μmol) indichloromethane (DCM) (1 mL) under nitrogen was added trifluoroaceticacid (0.25 mL, 3.24 mmol). The mixture was stirred at rt for 45 min.

The reaction mixture was allowed to stir for a further 15 min. Thereaction mixture was concentrated in vacuo and the residue thendissolved in methanol and loaded onto a 1 g SCX SPE cartridge, which hadbeen pre-equilibrated with methanol. The column was eluted withmethanol, and then 2M NH₃ in methanol. The appropriate fraction wascollected and concentrated in vacuo to afford the product (4.4 mg, 9.25μmol, 95%). This was a mixture of diastereoisomers.

LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=476.

Example 229:6-(((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

To a stirring solution of (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 186, 7.0 mg, 0.013 mmol) indichloromethane (DCM) (1. mL) under nitrogen was added trifluoroaceticacid (0.25 mL, 3.24 mmol). The mixture was stirred at rt for 45 min. Thereaction mixture was concentrated in vacuo. The residue was dissolved inmethanol and loaded onto a 1 g SCX SPE cartridge which had beenpre-equilibrated with methanol. The column was eluted with methanol intoone fraction, and then the product was eluted with 2M NH₃ in methanolinto a separate fraction. The appropriate fraction was concentrated invacuo to afford the product (2.3 mg, 5.17 μmol, 40.3%). This was amixture of diastereoisomers.

LCMS (2 min Formic): Rt=0.71 min, [MH]⁺=445.

Example 230:rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of 6-chloronicotinonitrile (25.4 mg, 0.183 mmol), DavePhos(6.00 mg, 0.015 mmol), Pd₂(dba)₃ (7 mg, 7.64 μmol), sodium tert-butoxide(29.3 mg, 0.305 mmol) andrac-(2S,3R,4R)-1-acetyl-4-amino-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 189, 42 mg, 0.153 mmol) in1,4-dioxane (3 mL) was stirred under nitrogen at 90° C. for 64 h. Afurther portion of Pd₂(dba)₃ (7 mg, 7.64 μmol) was added and the mixturestirred at 90° C. for a further 3 h. The reaction mixture was allowed tocool to rt, diluted with 5 mL MeOH, filtered through a cotton wool plugand evaporated to dryness under reduced pressure. The residue waspurified by MDAP (Formic) to afford the desired product as a pale yellowsolid (3.6 mg).

LCMS (2 min Formic): Rt=0.71 min, [MH]⁺=378.

Example 231:rac-(2S,3R,4R)-1-acetyl-N,2,3-trimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of 2-bromo-6-methylpyridine (31.5 mg, 0.183 mmol), DavePhos(6.00 mg, 0.015 mmol), Pd₂(dba)₃ (7 mg, 7.64 μmol), sodium tert-butoxide(29.3 mg, 0.305 mmol) andrac-(2S,3R,4R)-1-acetyl-4-amino-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 189, 42 mg, 0.153 mmol) in1,4-dioxane (3 mL) was stirred under nitrogen at 90° C. for 64 h. Afurther portion of Pd₂(dba)₃ (7 mg, 7.64 μmol) was added and the mixturestirred at 90° C. for a further 3 h. The reaction mixture was allowed tocool to rt, diluted with 5 mL MeOH, filtered through a cotton wool plugand evaporated to dryness under reduced pressure. The residue waspurified by MDAP (Formic) to afford the desired product as a pale yellowsolid (4.4 mg).

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=367.

Example 232:rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution ofrac-(2S,3R,4R)-1-acetyl-4-amino-N,2,3-trimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation, see Intermediate 189, 37 mg, 0.134 mmol) in NMP (1mL) was added 5-chloropyrazine-2-carbonitrile (37.5 mg, 0.269 mmol), andDIPEA (0.070 mL, 0.403 mmol) and the resultant solution heated to 150°C. for 30 min by microwave irradiation. The reaction mixture wasdirectly purified by MDAP (Formic) to afford the desired product as ayellow solid (11 mg). LCMS (2 min Formic): Rt=0.69 min, [M−H]⁻=377.

Example 233:rac-(2S,3R,4R)-1-acetyl-2-ethyl-N,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of 2-bromo-5-methylpyrazine (27.3 mg, 0.158 mmol), DavePhos(5.2 mg, 0.013 mmol), Pd₂(dba)₃ (7 mg, 7.64 μmol), sodium tert-butoxide(25.2 mg, 0.263 mmol) andrac-(2S,3R,4R)-1-acetyl-4-amino-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 192, 38 mg, 0.131 mmol) in1,4-dioxane (3 mL) was stirred under a nitrogen atmosphere at 90° C. for16 h. The reaction mixture was diluted with 5 mL MeOH and filteredthrough a plug of cotton wool. The solvent was removed by evaporation togive a residue which was purified by MDAP (Formic) to afford the desiredproduct as a pale brown solid (5.4 mg).

LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=382.

Example 234:rac-(2S,3R,4R)-1-acetyl-2-ethyl-N,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of 2-bromo-4-methylpyrimidine (27.3 mg, 0.158 mmol), DavePhos(5.2 mg, 0.013 mmol), Pd₂(dba)₃ (7 mg, 7.64 μmol), sodium tert-butoxide(25.2 mg, 0.263 mmol) andrac-(2S,3R,4R)-1-acetyl-4-amino-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 192, 38 mg, 0.131 mmol) in1,4-dioxane (3 mL) was stirred under a nitrogen atmosphere at 90° C. for16 h. The reaction mixture was diluted with 5 mL MeOH and filteredthrough a plug of cotton wool. The solvent was removed by evaporation togive a residue which was purified by MDAP (Formic) to afford the desiredproduct as a pale brown solid (3.0 mg).

LCMS (2 min Formic): Rt=0.64 min, [MH]⁺=382.

Example 235:rac-(2S,3R,4R)-1-acetyl-2-ethyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of 2-bromo-6-methylpyridine (27.1 mg, 0.158 mmol), DavePhos(5.2 mg, 0.013 mmol), Pd₂(dba)₃ (7 mg, 7.64 μmol), sodium tert-butoxide(25.2 mg, 0.263 mmol) andrac-(2S,3R,4R)-1-acetyl-4-amino-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation, see Intermediate 192, 38 mg, 0.131 mmol) in1,4-dioxane (3 mL) was stirred under a nitrogen atmosphere at 90° C. for16 h. The reaction mixture was diluted with 5 mL MeOH and filteredthrough a plug of cotton wool. The solvent was removed by evaporation togive a residue which was purified by MDAP (Formic) to afford the desiredproduct as a pale brown solid (7.8 mg).

LCMS (2 min Formic): Rt=0.55 min, [MH]⁺=381.

Example 236:rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution ofrac-(2S,3R,4R)-1-acetyl-4-amino-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 192, 37 mg, 0.128 mmol) in NMP (1mL) was added 5-chloropyrazine-2-carbonitrile (35.7 mg, 0.256 mmol), andDIPEA (0.067 mL, 0.384 mmol) and the resultant solution then heated to150° C. for 30 min by microwave irradiation. The reaction mixture wasdirectly purified by MDAP (Formic) to afford the desired product as ayellow solid (24.1 mg). LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=393.

Example 237:rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution ofrac-(2S,3R,4R)-1-acetyl-4-amino-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation, see Intermediate 192, 37 mg, 0.128 mmol) in NMP (1mL) was added 6-chloronicotinonitrile (35.4 mg, 0.256 mmol), and DIPEA(0.067 mL, 0.384 mmol) and the resultant solution then heated to 150° C.for 3 h 30 min by microwave irradiation. The reaction mixture wasdirectly purified by MDAP (Formic) to afford the desired product as ayellow solid (4.8 mg). LCMS (2 min Formic): Rt=0.76 min, [MH]⁺=392.

Example 238:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel containingrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonylchloride (for a preparation see Intermediate 196, 93 mg, 0.234 mmol).Methylamine 2M in THE (5 mL, 10.00 mmol) and DIPEA (1.225 mL, 7.01 mmol)were added and the reaction left to stir for 15 min at rt under N₂. Thesolution was concentrated in vacuo and retaken up in DCM (15 mL), thiswas washed with water (2×15 ml) and separated. The organic layer wasdried and concentrated in vacuo to give 100 mg of an orange/brown solid.This was purified by chromatography on silica (10 g, eluting with 0-8%methanol/DCM over 15 CVs). The fractions containing product werecombined and concentrated in vacuo to give 78 mg of product. This was ofinsufficient purity so was purified by chromatography on silica (10 g,eluting with 0-100% EtOAc/DCM). The fractions containing pure productwere combined and concentrated in vacuo to give 40 mg of product. Thefractions containing product with some impurities present were combinedand concentrated in vacuo to give 34 mg of impure product. This wasdissolved in 1:1 MeOH:DMSO 1 mL and purified by MDAP (HpH). The solventwas evaporated in vacuo to give 8 mg of product (8 mg, 0.020 mmol,8.72%) as a white solid.

LCMS (2 min formic): Rt=0.61 min, [MH]⁺=393.

Example 239a & 239b:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide(239a) &(2R,3S,4S)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide(239b)

rac-(2S,3R,4R)-1-Acetyl-2-cyclopropyl-N,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Example 238, ˜32 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×20 mm Chiralpak IAcolumn eluting with 10% ethanol in heptane at a flow rate of 20 mL/min.Peak 1/Enantiomer A fractions were collected between 8 and 9.5 min, andPeak 2/Enantiomer B fractions were collected between 11.5 and 13.5 min.Fraction solutions were combined and then evaporated to dryness to giveEnantiomer A (13 mg) and Enantiomer B (14 mg) as white solids.

Enantiomer A, Example 2391a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IA column elutingwith 10% ethanol in heptane at 1 mL/min—Rt=15 min. >99% ee by UV.

Enantiomer B, Example 239b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IA column elutingwith 10% ethanol in heptane at 1 mL/min—Rt=21.5 min, >99% ee by UV.

Example 240:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel 2-bromo-4-methylpyrimidine (88 mg, 0.509 mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for preparation see intermediate 200, 80 mg, 0.265 mmol), sodiumtert-butoxide (77 mg, 0.796 mmol), in 1,4-Dioxane (5 mL) were added. Thesolution was treated with Pd₂(dba)₃ (36.5 mg, 0.040 mmol) and DavePhos(20.89 mg, 0.053 mmol) and left to stir at 100° C. for 16 h under N₂.The reaction mixture was filtered through celite and the celite washedwith ethyl acetate. The combined filtrates were washed with water, theorganic phase was passed through a hydrophobic frit and concentrated invacuo to give a crude solid. This solid was purified by MDAP (Formic) togive a solid which was eluted through a NH₂ SPE (5 g) with MeOH, theeluent was concentrated to the product (14 mg, 0.036 mmol, 13.40%) as awhite solid. LCMS (2 min Formic): Rt=0.68 min, [MH]⁺=394.

Example 241:rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel 6-fluoronicotinonitrile (64.8 mg, 0.531 mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for preparation see Intermediate 200, 80 mg, 0.265 mmol) and DIPEA(0.139 mL, 0.796 mmol) were added and the reaction irradiated in amicrowave at 200° C. for 30 min. The reaction was purified directly byMDAP (Formic) to give a crude solid. This solid was purified by MDAP(Formic) to give a solid which was eluted through a NH₂ SPE (5 g) withMeOH, the eluent was concentrated to the product (47 mg, 0.116 mmol,43.9%) as a white solid. LCMS (2 min Formic): Rt=0.80 min, [MH]⁺=404.

Example 242:rac-(2S,3R,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a microwave vial 5-chloropyrazine-2-carbonitrile (74.1 mg, 0.531mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for preparation see Intermediate 200, 80 mg, 0.265 mmol), and DIPEA(0.139 mL, 0.796 mmol) were added and the reaction irradiated at 200° C.in a microwave for 30 mins. The reaction was purified directly using aMDAP (Formic) to give a beige solid. This solid was eluted through a NH₂SPE (5 g) with MeOH, the eluent was concentrated to the product (63 mg,0.156 mmol, 58.7%) as a beige solid.

LCMS (2 min Formic): Rt=0.78 min, [MH]⁺=405.

Example 243:rac-(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel 4-bromobenzonitrile (88 mg, 0.483 mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for preparation see Intermediate 200, 80 mg, 0.265 mmol), sodiumtert-butoxide (77 mg, 0.796 mmol), in 1,4-Dioxane (5 mL) were added. Thesolution was treated with Pd₂(dba)₃ (36.5 mg, 0.040 mmol) and DavePhos(20.89 mg, 0.053 mmol) and left to stir at 100° C. for 3 h under N₂. Themixture was allowed to cool to rt and then filtered through celite andthe celite washed with ethyl acetate. The combined filtrates were washedwith brine, the organic phase was dried through a hydrophobic frit andconcentrated to give a orange gum. This gum was purified using a MDAP(Formic) to give a white solid. This solid was eluted through a NH₂ SPE(5 g) with MeOH, the eluent was concentrated to give the product (5 mg,0.012 mmol, 4.68%) as a white solid. LCMS (2 min Formic): Rt=0.87 min,[MH]⁺=403.

Example 244:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel 2-bromo-5-fluoropyridine (90 mg, 0.511 mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for preparation see Intermediate 200, 80 mg, 0.265 mmol), sodiumtert-butoxide (77 mg, 0.796 mmol), in 1,4-dioxane (5 mL) were added. Thesolution was treated with Pd₂(dba)₃ (36.5 mg, 0.040 mmol) and DavePhos(20.89 mg, 0.053 mmol) and left to stir at 100° C. for 3 h under N₂. Thereaction was treated with further 2-bromo-5-fluoropyridine (80 mg, 0.455mmol), DavePhos (14 mg, 0.036 mmol), Pd₂(dba)₃ (18 mg, 0.020 mmol) andsodium tert-butoxide (50 mg, 0.520 mmol) and the reaction left to stirat 100° C. for 16 h under N₂. The reaction mixture was allowed to coolto rt and then filtered through celite and the celite washed with ethylacetate. The combined filtrates were washed with brine solution theorganic phase was dried through a hydrophobic frit and concentrated togive a crude brown gum (333 mg). This gum was purified by MDAP (Formic)to give a white solid. This solid was eluted through a NH₂ SPE (5 g)with MeOH, the eluent was concentrated and dried to give the product (34mg). LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=397.

Example 245:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel 2-bromo-6-methoxypyridine (0.06 mL, 0.488 mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for preparation se Intermediate 200, 80 mg, 0.265 mmol), sodiumtert-butoxide (77 mg, 0.796 mmol), in 1,4-dioxane (5 mL) were added. Thesolution was treated with Pd₂(dba)₃ (36.5 mg, 0.040 mmol) and DavePhos(20.89 mg, 0.053 mmol) and left to stir at 100° C. for 3 h under N₂. Thereaction was allowed to cool to rt and then filtered through celite andthe celite washed with ethyl acetate. The combined filtrates were washedwith brine the organic phase was dried through a hydrophobic frit andconcentrated in vacuo to give a crude brown gum. This was purified bycolumn chromatography on silica gel, eluting with 0-100% ethylacetate/cyclohexane to give the product as an orange gum (49 mg, 86%pure). This gum could be purified by MDAP (Formic) to give a solid. Thissolid was eluted through a NH₂ SPE (5 g) with MeOH, the eluent wasconcentrated to give the product (7 mg).

LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=409.

Example 246:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-N,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel 2-chloro-5-methylpyrazine (81 mg, 0.630 mmol),rac-(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for preparation see Intermediate 200, 80 mg, 0.265 mmol), sodiumtert-butoxide (77 mg, 0.796 mmol), in 1,4-dioxane (5 mL) were added. Thesolution was treated with Pd₂(dba)₃ (36.5 mg, 0.040 mmol) and DavePhos(20.89 mg, 0.053 mmol) and left to stir at 100° C. for 2 h under N₂. Thereaction mixture was allowed to cool to rt and then filtered throughcelite and the celite washed with ethyl acetate. The combined filtrateswere concentrated in vacuo to give a crude orange/brown gum. This gumwas purified by MDAP (Formic) to give a solid, this solid was elutedthrough a NH₂ SPE (5 g) with MeOH, the eluent was concentrated to givethe product (59 mg, 0.150 mmol, 56.5%) as a beige solid.

LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=394.

Example 247:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

Sodium tert-butoxide (1.968 g, 20.48 mmol), Pd₂(dba)₃ (0.313 g, 0.341mmol), DavePhos (0.269 g, 0.683 mmol), and (2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 2.16 g, 6.83 mmol) weredissolved in 1,4-dioxane (136 mL). 2-bromo-6-methylpyridine (0.932 mL,8.19 mmol) was added and the reaction stirred for 1 h under N₂ at 100°C. The reaction mixture was cooled to rt, filtered through celite(washed with EtOAc) and the filtrates concentrated in vacuo. The residuewas taken up in EtOAc (75 mL) and saturated sodium bicarbonate solution(100 mL), the organic layer was discarded. The aqueous layer wasacidified to pH1 with 2M hydrochloric acid (250 mL) and extractedmultiple times with EtOAc, DCM and chloroform. The combined organicswere dried using a hydrophobic frit and evaporated in vacuo to give (theproduct (555 mg) as a yellow solid. The aqueous was evaporated todryness, taken up in MeOH (50 mL), filtered and evaporated to affordcrude product that was added to a silica gel column and was eluted with10-20% 2M NH3 in methanol/DCM. Fractions containing product wereevaporated to afford the product (450 mg) as a yellow oil. LCMS (2 minHpH): Rt=0.68 min, [MH]⁺=380.

Example 248:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was addedethylamine (2M in THF, 80 μL, 0.158 mmol) followed by DIPEA (0.097 mL,0.553 mmol). The reaction mixture was stirred at rt for 90 min, thenpurified directly by MDAP (HpH). The solvent was evaporated in vacuo togive the product (15 mg). LCMS (2 min HpH): Rt=0.96 min, [MH]⁺=407.

Example 249:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-propyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was addedpropylamine (14 μL, 0.158 mmol) followed by DIPEA (0.097 mL, 0.553mmol). The reaction mixture was stirred at rt for 90 min, then purifieddirectly by MDAP (HpH). The solvent was evaporated in vacuo to give theproduct (29 mg). LCMS (2 min HpH): Rt=1.03 min, [MH]⁺=421.

Example 250:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(pyrrolidine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was addedpyrrolidine (13 μL, 0.158 mmol) followed by DIPEA (0.097 mL, 0.553mmol). The reaction mixture was stirred at rt for 90 min, then purifieddirectly by MDAP (Hph). The solvent was evaporated in vacuo to give theproduct (14 mg). LCMS (2 min HpH): Rt=1.00 min, [MH]⁺=433.

Example 251:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(morpholine-4-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was addedpyrrolidine (13 μL, 0.158 mmol) followed by DIPEA (0.097 mL, 0.553mmol). The reaction mixture was stirred at rt for 90 min, then purifieddirectly by MDAP (HpH). The solvent was evaporated in vacuo to give theproduct (32 mg). LCMS (2 min HpH): Rt=0.92 min, [MH]⁺=449.

Example 252:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-6-(morpholine-4-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was addedtetrahydro-2H-pyran-4-amine (16 μL, 0.158 mmol) followed by DIPEA (0.097mL, 0.553 mmol). The reaction mixture was stirred at rt for 90 min, thenpurified directly by MDAP (HpH). The solvent was evaporated in vacuo togive the product (38 mg). LCMS (2 min HpH): Rt=0.94 min, [MH]⁺=463.

Example 253:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was addedpyridin-3-ylmethanamine (16 μL, 0.158 mmol) followed by DIPEA (0.097 mL,0.553 mmol). The reaction mixture was stirred at rt for 90 min, thenpurified directly by MDAP (HpH). The solvent was evaporated in vacuo togive the product (37 mg). LCMS (2 min HpH): Rt=0.93 min, [MH]⁺=470.

Example 254:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added1H-pyrazol-4-amine (13 mg, 0.158 mmol) followed by DIPEA (0.097 mL,0.553 mmol). The reaction mixture was stirred at rt for 90 min, thenpurified directly by MDAP (HpH). The solvent was evaporated in vacuo togive the product (8 mg). LCMS (2 min High pH): Rt=0.88 min, [MH]⁺=445.

Example 255:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(2-morpholinoethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added2-morpholinoethanamine (21 μL, 0.158 mmol) followed by DIPEA (0.097 mL,0.553 mmol). The reaction mixture was stirred at rt for 90 min, thenpurified directly by MDAP (HpH). The solvent was evaporated in vacuo togive the product (48 mg). LCMS (2 min HpH): Rt=0.90 min, [MH]⁺=492.

Example 256:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added2-methoxyethanamine (14 μL, 0.158 mmol) followed by DIPEA (0.097 mL,0.553 mmol). The reaction mixture was stirred at rt for 90 min, thenpurified directly by MDAP (HpH). The solvent was evaporated in vacuo togive the product (32 mg). LCMS (2 min HpH): Rt=0.94 min, [MH]⁺=437.

Example 257:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-methoxyethyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.132 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added2-aminoethanol (10 μL, 0.158 mmol) followed by DIPEA (0.097 mL, 0.553mmol). The reaction mixture was stirred at rt for 90 min, then purifieddirectly by MDAP (HpH). The solvent was evaporated in vacuo to give theproduct (39 mg). LCMS (2 min HpH): Rt=0.84 min, [MH]⁺=423.

Example 258:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 50 mg, 0.791 mmol) and HATU (90mg, 0.198 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added4-aminotetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (30 mg, 0.158mmol) followed by DIPEA (0.097 mL, 0.553 mmol). The reaction mixture wasstirred at rt for 90 min, then purified directly by MDAP (HpH) Thesolvent was evaporated in vacuo to give the product (45 mg).

LCMS (2 min HpH): Rt=0.91 min, [MH]⁺=511.

Example 259:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A suspension of tert-butyl(2-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamido)ethyl)(methyl)carbamate(for a preparation see Intermediate 226, 117 mg, 0.218 mmol) in HCl (4Min 1,4-dioxane) (5 mL, 20.00 mmol) was stirred at rt for 18 hr. Thesolvent and excess HCl were removed under reduced pressure and the crudewas purified by MDAP (HpH). The solvent was evaporated in vacuo to givethe product (17 mg).

LCMS (2 min HpH): Rt=0.85 min, [MH]⁺=436.

Example 260:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-((S)-tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 25 mg, 0.066 mmol) and HATU (38mg, 0.99 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added(S)-tetrahydrofuran-3-amine hydrochloride (10 mg, 0.08 mmol) followed byDIPEA (0.055 mL, 0.316 mmol). The reaction mixture was stirred at rt for90 min, then purified directly by MDAP (HpH). The solvent was evaporatedin vacuo to give the product (18 mg). LCMS (2 min HpH): Rt=0.93 min,[MH]⁺=449.

Example 261:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-((R)-tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 25 mg, 0.066 mmol) and HATU (38mg, 0.99 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added(R)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate (21 mg, 0.08 mmol)followed by DIPEA (0.055 mL, 0.316 mmol). The reaction mixture wasstirred at rt for 90 min, then purified directly by MDAP (HpH). Thesolvent was evaporated in vacuo to give the product (14 mg).

LCMS (2 min HpH): Rt=0.93 min, [MH]⁺=449.

Example 262:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 25 mg, 0.066 mmol) and HATU (38mg, 0.99 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added2-(methylsulfonyl)ethanamine hydrochloride (13 mg, 0.08 mmol) followedby DIPEA (0.055 mL, 0.316 mmol). The reaction mixture was stirred at rtfor 90 min, then purified directly by MDAP (HpH). The solvent wasevaporated in vacuo to give the product (13 mg).

LCMS (2 min HpH): Rt=0.89 min, [MH]⁺=485.

Example 263:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxypropyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 705 mg, 0.184 mmol) and HATU(84 mg, 0.221 mmol) in N,N-dimethylformamide (DMF) (2 mL) was added1-aminopropan-2-ol (0.017 mL, 0.221 mmol) and DIPEA (0.129 mL, 0.738mmol). The reaction mixture was stirred at rt for 60 min, thenpartitioned between ether (25 mL) and water (50 mL) and the aqueousextracted with ether (3×25 mL). The combined organics were washed withbrine (10 mL), dried (MgSO₄) and evaporated in vacuo to afford theproduct (50 mg). This was a mixture of diastereoisomers.

LCMS (2 min HpH): Rt=0.87 min, [MH]⁺=437.

Example 264:rac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid, TFA salt

To a mixture of rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 203, 934 mg, 3.22 mmol), sodiumtert-butoxide (930 mg, 9.68 mmol), Pd₂(dba)₃ (150 mg, 0.164 mmol) andDavePhos (130 mg, 0.330 mmol) were added anhydrous 1,4-dioxane (15 mL)and 2-bromo-6-methylpyridine (0.40 mL, 3.52 mmol). The mixture wasevacuated and purged with nitrogen 3 times and stirred under nitrogen at100° C. for 1.5 h. The reaction mixture was allowed to cool to rt andfiltered through celite. The cake was washed with EtOAc (60 mL). Thesolvent was concentrated in vacuo and the gum dissolved in MeOH (5 mL).The solution was applied to a MeOH-preconditioned 20 g SCX-2 cartridgewhich was then washed with MeOH (60 mL) followed by 2M ammonia in MeOHsolution (60 mL). The basic wash was evaporated in vacuo and the browngum purified by MDAP (TFA). The appropriate fractions were combined andthe solvent removed by rotary evaporation to give the title compound asa yellow gum (496 mg, 1.061 mmol, 33%). LCMS (2 min HpH): Rt=0.62 min,[MH]⁺=354.

Examples 265-276: amide array ofrac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid, TFA salt (Example 264)

Monomers

Reagent Reagent Reagent Volume Ex No. Name Structure MW Mass (g) (mL)mmol 265 2- aminoethanol

61.08 — 0.012 0.198 266 ethanamine

45.08 — 0.099 0.198 267 tert-butyl 4- amino- piperidine-1- carboxylate

200.28 0.040 — 0.200 268 tert-butyl(2- aminoethyl) (methyl) carbamate

174.24 — 0.035 0.195 269 2- methoxy- ethanamine

75.11 — 0.017 0.200 270 3- amino- propanenitrile

70.09 0.014 — 0.200 271 2- morpholino- ethanamine

130.19 — 0.026 0.200 272 propan-2- amine

59.11 — 0.017 0.203 273 tetrahydro- 2H-pyran-4- amine

101.15 — 0.020 0.198 274 4- aminotetra- hydro-2H- thiopyran 1,1-dioxidehydrochloride

183.05 0.036 — 0.194 275 morpholine

87.12 — 0.017 0.195 276 tert-butyl 3- amino- pyrrolidine-1- carboxylate

186.25 — 0.036 0.199

A mixture ofrac-(2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid,trifluoroacetic acid salt (fora preparation see Example 264, 444 mg,0.95 mmol) and HATU (900 mg, 2.37 mmol) was suspended in anhydrous DMF(6.0 mL) and treated with DIPEA (0.420 mL, 3.24 mmol). The mixture wasallowed to stand in a stoppered vessel at rt for 10 min then dispensedevenly (˜0.54 mL) into each amine. (Note: Further DIPEA (0.035 mL, 0.198mmol) was added to reaction 274). The mixtures were left to stand instoppered vessels at rt for 15 h. The reaction mixtures were dilutedwith MeOH (0.25 mL) and purified on a Waters CSH C18 column (150 mm×30mm, 5 μm packing diameter) at 40 mL/min flow rate. Gradient elution wascarried out with acetonitrile in the mobile phases as (A) 10 mM ammoniumbicarbonate in water solution, adjusted to pH 10 with 0.88 ammoniasolution and (B) acetonitrile. The UV detection was a summed signal fromwavelength of 210 nm to 400 nm. The appropriate fractions were combinedand evaporated. Samples from reactions 267, 268 & 276 were dissolved inDCM (0.4 mL) and treated with TEA (0.2 mL) and the solutions left tostand in stoppered vessels at rt for 30 min. The reaction mixtures wereevaporated under a stream of nitrogen and the residues dissolved in MeOH(0.4 mL). The solutions were applied to MeOH-preconditioned 0.5 g SCX-2cartridges which were then washed with MeOH (3 mL) followed by 2Mammonia in MeOH solution (3 mL). The basic washes were evaporated undera stream of nitrogen to give final deprotected compounds.

EXAMPLES

Mass Yield Ex No. Name Structure (mg) (%) [MH]⁺ Rt (min)* 265rac-(2S,3R,4R)-1- acetyl-N-(2- hydroxyethyl)-2,3- dimethyl-4-((6-methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

23 73 397 0.76 266 rac-(2S,3R,4R)-1- acetyl-N-ethyl-2,3- dimethyl-4-((6-methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

24 80 381 0.88 267 rac-(2S,3R,4R)-1- acetyl-2,3- dimethyl-4-((6-methylpyridin-2- yl)amino)-N- (piperidin-4-yl)- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

20 58 436 0.77 268 rac-(2S,3R,4R)-1- acetyl-2,3- dimethyl-N-(2-(methylamino) ethyl)-4-((6- methylpyridin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

21 65 410 0.77 269 rac-(2S,3R,4R)-1- acetyl-N-(2- methoxyethyl)-2,3-dimethyl-4-((6- methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

27 83 411 0.85 270 rac-(2S,3R,4R)-1- acetyl-N-(2- cyanoethyl)-2,3-dimethyl-4-((6- methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

14 44 406 0.84 271 rac-(2S,3R,4R)-1- acetyl-2,3- dimethyl-4-((6-methylpyridin-2- yl)amino)-N-(2- morpholinoethyl)- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

31 84 466 0.83 272 rac-(2S,3R,4R)-1- acetyl-N- isopropyl-2,3-dimethyl-4-((6- methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

26 83 395 0.94 273 rac-(2S,3R,4R)-1- acetyl-2,3- dimethyl-4-((6-methylpyridin-2- yl)amino)-N- (tetrahydro-2H- pyran-4-yl)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

29 84 437 0.86 274 rac-(2S,3R,4R)-1- acetyl-N-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)- 2,3-dimethyl-4-((6- methylpyridin-2-yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

29 76 485 0.83 275 rac-1-((2S,3R,4R)- 2,3-dimethyl-4-((6-methylpyridin-2- yl)amino)-6- (morpholine-4- carbonyl)-3,4-dihydroquinolin- 1(2H)-yl)ethanone

25 75 423 0.84 276 (rac-2S,3R,4R)-1- acetyl-2,3- dimethyl-4-((6-methylpyridin-2- yl)amino)-N- (pyrrolidin-3-yl)- 1,2,3,4-tetrahydroquinoline- 6-carboxamide; racemic mixture of diatereoisomers.

20 60 422 0.76 *All LCMS were conducted using 2 min HpH.

Example 277:rac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid, TFA salt

To a mixture of rac-(2S,3R,4R)-ethyl1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 206, 1.62 g, 5.32 mmol), sodiumtert-butoxide (1.534 g, 15.97 mmol), Pd₂(dba)₃ (0.244 g, 0.266 mmol) andDavePhos (0.210 g, 0.534 mmol) were added anhydrous 1,4-dioxane (20 mL)and 2-bromo-6-methylpyridine (0.727 mL, 6.39 mmol). The mixture wasevacuated and purged with nitrogen 3 times and stirred under nitrogen at100° C. for 1.5 h. The reaction mixture was allowed to cool to rt andfiltered through celite. The cake was washed with EtOAc (80 mL). Thesolvent was concentrated in vacuo and the gum dissolved in MeOH (5 mL).The solution was applied to a MeOH-preconditioned 50 g SCX-2 cartridgewhich was then washed with MeOH (100 mL) followed by 2M ammonia in MeOHsolution (100 mL). The basic wash was evaporated in vacuo to give browngum. The gum was purified by MDAP (TEA). The appropriate fractions werecombined and the solvent removed by rotary evaporation to give the titlecompound as a yellow gum (1.01 g, 2.098 mmol, 39%). LCMS (2 min HpH):Rt=0.65 min [MH]⁺=368.

Examples 278-289: amide array ofrac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid, TFA salt (Example 277)

Monomers

Reagent Reagent Reagent Mass Volume Ex No. Name Structure MW (mg) (mL)mmol 278 2- aminoethanol

61.08 — 0.015 0.246 279 ethanamine

45.08 — 0.126 0.252 280 tert-butyl 4- aminopiperi- dine-1- carboxylate

200.28 0.050 — 0.250 281 tert-butyl(2- aminoethyl) (methyl) carbamate

174.24 — 0.045 0.253 282 2- methoxyeth- anamine

75.11 — 0.022 0.253 283 3- aminopro- panenitrile

70.09 0.018 — 0.257 284 2- morpholino ethanamine

130.19 — 0.033 0.253 285 propan-2- amine

59.11 — 0.021 0.254 286 tetrahydro- 2H-pyran-4- amine

101.15 — 0.026 0.247 287 4- aminotetra- hydro-2H- thiopyran 1,1-dioxidehydrochloride

183.05 0.046 — 0.251 288 morpholine

87.12 — 0.022 0.253 289 tert-butyl 3- aminopyrroli- dine-1- carboxylate

186.25 — 0.046 0.252

A mixture ofrac-(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid, TEA salt (for a preparation see Example 277, 444 mg, 0.922 mmol)and HATU (1.15 g, 3.03 mmol) was suspended in anhydrous DMF (6.0 mL) andtreated with DIPEA (0.528 mL, 4.09 mmol). The mixture was allowed tostand in a stoppered vessel at rt for 10 min then dispensed evenly(˜0.54 mL) into each amine. (Note: Further DIPEA (0.044 mL, 0.254 mmol)was added to reaction). The mixtures were left to stand in stopperedvessels at rt for 15 h. The reaction mixtures were diluted with MeOH(0.25 mL) and purified on a Waters CSH C18 column (150 mm×30 mm, 5 μmpacking diameter) at 40 mL/min flow rate. Gradient elution was carriedout with acetonitrile in the mobile phases as (A) 10 mM ammoniumbicarbonate in water solution, adjusted to pH 10 with 0.88 ammoniasolution and (B) acetonitrile. The UV detection was a summed signal fromwavelength of 210 nm to 400 nm. The appropriate fractions were combinedand evaporated. Samples from reactions 280, 281 & 289 were dissolved inDCM (0.4 mL) and treated with TEA (0.2 mL) and the solutions left tostand in stoppered vessels at r.t. for 30 min. The reaction mixtureswere evaporated under a stream of nitrogen and the residues dissolved inMeOH (0.4 mL). The solutions were applied to MeOH-preconditioned 0.5 gSCX-2 cartridges which were then washed with MeOH (3 mL) followed by 2Mammonia in MeOH solution (3 mL). The basic washes were evaporated undera stream of nitrogen to give final deprotected compounds.

The following compounds of formula (I) were also prepared:

Mass Yield Rt Ex No. Name Structure (mg) (%) [MH]⁺ (min)* 278rac-(2S,3R,4R)- 1-acetyl-2-ethyl- N-(2- hydroxyethyl)- 3-methyl-4-((6-methylpyridin- 2-yl)amino)- 1,2,3,4- tetrahydroquino- line-6-carboxamide

28 89 411 0.81 279 rac-(2S,3R,4R)- 1-acetyl-N,2- diethyl-3-methyl-4-((6- methylpyridin- 2-yl)amino)- 1,2,3,4- tetrahydroquino-line-6- carboxamide

25 82 395 0.93 280 rac-(2S,3R,4R)- 1-acetyl-2-ethyl- 3-methyl-4-((6-methylpyridin- 2-yl)amino)-N- (piperidin-4-yl)- 1,2,3,4-tetrahydroquino- line-6- carboxamide

25 72 450 0.83 281 rac-(2S,3R,4R)- 1-acetyl-2-ethyl- 3-methyl-N-(2-(methylamino) ethyl)-4-((6- methylpyridin- 2-yl)amino)- 1,2,3,4-tetrahydroquino- line-6- carboxamide

24 73 424 0.82 282 rac-(2S,3R,4R)- 1-acetyl-2-ethyl- N-(2-methoxyethyl)- 3-methyl-4-((6- methylpyridin- 2-yl)amino)- 1,2,3,4-tetrahydroquino- line-6- carboxamide

23 70 425 0.90 283 rac-(2S,3R,4R)- 1-acetyl-N-(2- cyanoethyl)-2-ethyl-3-methyl- 4-((6- methylpyridin- 2-yl)amino)- 1,2,3,4-tetrahydroquino- line-6- carboxamide

13 40 420 0.90 284 rac-(2S,3R,4R)- 1-acetyl-2-ethyl- 3-methyl-4-((6-methylpyridin- 2-yl)amino)-N- (2- morpholinoethyl)- 1,2,3,4-tetrahydroquino- line-6- carboxamide

28 76 480 0.87 285 rac-(2S,3R,4R)- 1-acetyl-2-ethyl- N-isopropyl-3-methyl-4-((6- methylpyridin- 2-yl)amino)- 1,2,3,4- tetrahydroquino-line-6- carboxamide

23 73 409 0.99 286 rac-(2S,3R,4R)- 1-acetyl-2-ethyl- 3-methyl-4-((6-methylpyridin- 2-yl)amino)-N- (tetrahydro-2H- pyran-4-yl)- 1,2,3,4-tetrahydroquino- line-6- carboxamide

28 81 451 0.91 287 rac-(2S,3R,4R)- 1-acetyl-N-(1,1- dioxidotetra-hydro-2H- thiopyran-4-yl)- 2-ethyl-3- methyl-4-((6- methylpyridin-2-yl)amino)- 1,2,3,4- tetrahydroquino- line-6- carboxamide

30 78 499 0.87 288 rac-1- ((2S,3R,4R)-2- ethyl-3-methyl- 4-((6-methylpyridin- 2-yl)amino)-6- (morpholine-4- carbonyl)-3,4-dihydroquinolin- 1(2H)- yl)ethanone

20 60 437 0.89 289 (rac-2S,3R,4R)- 1-acetyl-2-ethyl- 3-methyl-4-((6-methylpyridin- 2-yl)amino)-N- (pyrrolidin-3-yl)- 1,2,3,4-tetrahydroquino- line-6- carboxamide; racemic mixture of diatereoisomers

23 69 436 0.81 *All LCMS were conducted using 2 min HpH.

Example 290:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylthiazol-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution ofrac-1-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)thiourea(for a preparation see Intermediate 207, 65 mg, 0.214 mmol) and conc.HCl (0.325 μL, 10.71 μmol) in ethanol (3 mL) stirred at rt was added1-chloropropan-2-one (0.020 mL, 0.257 mmol). The reaction mixture washeated to 80° C. for 2 h, then evaporated and the residue redissolved inEtOAc (10 mL) and sat. aq. NaHCO₃ (10 mL). The aqueous layer was washedwith EtOAc (10 mL) and the combined organics washed with brine, dried(MgSO₄) and evaporated. Purification by silica chromatography (40-60%EtOAc/cyclohexane) gave the product (65 mg) as a clear oil.

LCMS (2 min HpH): Rt=1.02 min, [MH]⁺=342.

Example 291:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 292, 1.036 g, 2.72 mmol) inN,N-dimethylformamide (DMF) (20 ml) was added HATU (1.056 g, 2.78 mmol)followed by DIPEA (0.951 ml, 5.45 mmol). The resulting reaction mixturewas stirred at room temperature under N₂ for 15 min. Ammonium chloride(0.291 g, 5.45 mmol) was then added and the reaction stirred for ˜1 h.The reaction mixture was quenched with brine (30 mL) and ethyl acetate(30 mL) was then added. A small amount of water (10 mL) was added tore-dissolve any inorganics and the resultant biphasic mixture allowed tosit overnight. The layers were separated and the aqueous layer furtherextracted with ethyl acetate (2×30 mL). The combined organics wereback-extracted with sat. aq. LiCl solution (3×20 mL). Product was foundto have partitioned into the aqueous layer. Therefore the aqueous layerwas diluted with brine (30 mL) and DCM (30 mL) was added. The layerswere separated and the aqueous layer further extracted with DCM (2×30mL). The combined DCM layers were combined with the earlier EtOAcwashings and the organics dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was taken up in DCM and added to a 100 g silica cartridgeand purified by flash chromatography, eluting with 0%->40% acetone/ethylacetate. Purer fractions were collected and concentrated in vacuo toafford the desired product as a cream foam (732 mg, 1.929 mmol, 70.8%).LCMS (2 min Formic): Rt=0.63 min, [MH]⁺=380.

Example 292:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 227, 29 g, 71.0 mmol) was taken upin tetrahydrofuran (THF) (175 mL) and water (175 mL). Lithium hydroxide(4.25 g, 177 mmol) was added and the reaction stirred at roomtemperature overnight. 2M HCl(aq) (89 mL, 177 mmol) was added followedby 10% MeOH/DCM (200 mL) and water (200 mL). The biphasic mixture wasstirred for 5 min and the layers then separated. The aqueous layer wasfurther extracted with 10% MeOH/DCM (2×200 mL) and the combined organicswere dried (MgSO₄), filtered and concentrated to leave the product as apale yellow foam (26.5 g).

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=381.

The following examples were prepared in a similar manner to Intermediate232 using Pd(QPhos)₂ and NaOtBu to couple the appropriate aryl halide toIntermediate 231.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)293 (2S,3R,4R)-1-acetyl-2- cyclopropyl-4-((3- methoxypyridin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6- carbonitrile

181 78 377 0.71 (2 min Formic) 294 (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl- 4-((4-methylpyridin-2- yl)amino)-1,2,3,4-tetrahydroquinoline-6- carbonitrile

117 53 361 0.68 (2 min Formic) 295 (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl- 4-((5-methylpyridin-2- yl)amino)-1,2,3,4-tetrahydroquinoline-6- carbonitrile

26 14 361 0.66 (2 min Formic) 296 (2S,3R,4R)-1-Acetyl-2-cyclopropyl-3-methyl- 4-((3-methylpyridin-2- yl)amino)-1,2,3,4-tetrahydroquinoline-6- carbonitrile

15 8 361 0.66 (2 min Formic)

The following examples were prepared in a similar manner to Intermediate234 using Pd₂(dba)₃, Q-Phos and NaOtBu to couple the appropriate arylhalide to Intermediate 231.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)297 (2S,3R,4R)-1- acetyl-2- cyclopropyl-3- methyl-4-((6-(morpholinomethyl) pyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carbonitrile

26 21 447 0.71 (2 min Formic) 298 (2S,3R,4R)-1- acetyl-2-cyclopropyl-4-((6- ((dimethylamino) methyl)pyridin-2- yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carbonitrile

210 93 405 0.71 (2 min Formic) 299 (2S,3R,4R)-1- acetyl-2-cyclopropyl-4-((5- methoxy-4- methylpyrimidin- 2-yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carbonitrile

79 27 392 1.02 (2 min HpH) 300 (2S,3R,4R)-1- acetyl-4-((5- chloro-4-methylpyrimidin- 2-yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

40 14 396 1.15 (2 min HpH) 301 (2S,3R,4R)-1- acetyl-2-cyclopropyl-4-((3- fluoropyridin-2- yl)amino)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

7 5 365 1.08 (2 min HpH)

The following examples were prepared in a similar manner to Intermediate239 using Pd₂(dba)₃, DavePhos, NaOtBu and the appropriate aryl halide in1,4-dioxane).

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)302 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((4- fluorophenyl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carbonitrile

55 33 364 1.13 (2 min Formic) 303 (28,3R,4R)-1-acetyl- 4-((4-chlorophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

13 18 380 1.22 (2 min Formic) 304 (2S,3R,4R)-1-acetyl- 4-((3-chlorophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

24 33 380 1.22 (2 min Formic) 305 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6- (methoxymethyl) pyridin-2-yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carbonitrile

38 26 391 0.75 (2 min Formic) 306 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((2- (methoxymethyl) phenyl)amino)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

67 46 390 1.20 (2 min Formic) 307 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3- fluorophenyl)amino)- 3-methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

51 54 364 1.14 (2 min Formic) 308 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4- methoxyphenyl) amino)-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carbonitrile

45 65 376 1.11 (2 min Formic) 309 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3- ethoxyphenyl)amino)- 3-methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

36 50 390 1.19 (2 min Formic)

The following examples were prepared in a similar manner to Intermediate161 using an SnAr reaction with DIPEA to couple the appropriate arylfluoride with Intermediate 231.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)310 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3- methyl-4-(pyrimidin-2-ylamino)-1,2,3,4- tetrahydroquinoline- 6-carbonitrile

102 61 348 0.84 (2 min Formic) 311 (2S,3R,4R)-1-acetyl-4-((3-cyanopyridin- 2-yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

109 61 365 1.01 (2 min Formic)

Example 312:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A solution of(2S,3R,4R)-1-acetyl-4-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 232, 50 mg, 0.102 mmol) in anhydrousTHE (0.5 mL) was treated with TBAF (0.5 mL, 0.500 mmol, 1 M solution inTHF) and the mixture allowed to stand at rt for 1.5 h. The reactionmixture was evaporated in vacuo and the residue purified by MDAP (HpH).The appropriate fractions were combined and the solvent removed byrotary evaporation to give the crude product as a white solid. This wasloaded in DCM (2 mL) and purified by flash chromatography on a silicacartridge (25 g) using a gradient of 0-15% MeOH in DCM over 10 CV. Theappropriate fractions were combined and the solvent removed by rotaryevaporation to give the title compound as a white solid (51 mg, 0.135mmol, 98%). LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=377.

Example 313:2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinicacid

A solution of methyl2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinate(for a preparation see Intermediate 242, 65 mg, 0.161 mmol) and LiOH(11.55 mg, 0.482 mmol) in tetrahydrofuran (1 mL) and water (1 mL) wasstirred in a closed vessel at rt for 16 h. The solution was diluted withHCl solution (5 mL, 0.5 M) and washed with DCM (3×5 mL). The organiclayers were combined and concentrated in vacuo to give2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinicacid (59 mg, 0.151 mmol, 94% yield). LCMS (2 min HpH): Rt=0.65 min,[MH]⁺=391.

Example 314:2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinamide

A solution of2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinicacid (for a preparation see Example 313, 50 mg, 0.128 mmol), HATU (63.3mg, 0.166 mmol), DIPEA (0.089 mL, 0.512 mmol) and ammonium chloride(20.55 mg, 0.384 mmol) in N,N-dimethylformamide (1 mL) was stirred in aclosed vessel at rt for 20 min. The solvent was evaporated under astream of nitrogen, the residue was then dissolved in 1:1 MeOH:DMSO (1mL) and purified by MDAP (Formic). The appropriate fractions werecombined and concentrated in vacuo to give the product (29.2 mg, 0.075mmol, 59%). LCMS (2 min HpH): Rt=0.88 min, [MH]⁺=390.

Example 315:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-(piperazin-1-ylmethyl)pyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile

In a 50 mL RB flask, 4M HCl in 1,4-dioxane (0.335 mL, 1.338 mmol) wasadded to a stirred solution of tert-butyl4-((6-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2-yl)methyl)piperazine-1-carboxylate(for a preparation see Intermediate 234, 24.3 mg, 0.045 mmol) in1,4-dioxane (3 mL). The resulting solution was left stirring for 1 h atrt. Further 4M HCl in 1,4-dioxane (0.167 mL, 0.669 mmol) was added andreaction mixture left stirring at rt for 2 h. The volatiles were removedunder reduced pressure to afford the crude product as a yellow gum (30.5mg). The resulting crude product was dissolved in MeOH and loaded onto a5 g SCX cartridge, this was washed with methanol (3 CV) and then flushedwith MeOH/NH₃ (2 M, 3CV). The ammonia fractions were combined and thevolatiles removed under reduced pressure to afford the title compound asa yellow gum (23.4 mg). An MDAP was carried out to further purify thecompound. Accordingly, the sample was dissolved in MeOH (0.9 mL) andpurified by MDAP (Formic). The appropriate fractions were combined andthe solvent was evaporated in vacuo to give the required product (12.3mg). LCMS (2 min Formic): Rt=0.55 min, [MH]⁺=445.

Example 316:6-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinamide

To a reaction vessel,6-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)picolinicacid (for a preparation see Intermediate 244, 200 mg, 0.512 mmol) andHATU (390 mg, 1.024 mmol) were taken up in N,N-dimethylformamide (4 mL).DIPEA (0.358 mL, 2.049 mmol) was added and the reaction left to stir for1 min at rt. Ammonium chloride (41.1 mg, 0.768 mmol) was then added andthe reaction left to stir at rt for 45 min and left to stand for 16 h.The reaction solution was diluted with ethyl acetate (35 mL) and washedwith 10% LiCl (aq, 2×40 mL) before being dried through a hydrophobicfrit and concentrated in vacuo to give the crude product as a brownsolid. This was purified by flash chromatography using a Biotage SNAP(10 g) silica cartridge, eluting with 0-3.5% methanol/DCM. The fractionscontaining product were combined and concentrated in vacuo to give thedesired product (109 mg). This was still impure so was redissolved in1:1 MeOH:DMSO (1 mL) and purified by MDAP (Formic). The solvent wasevaporated in vacuo to give the desired product as an off white solid.This was re-taken up in methanol and eluted through a pre-equilibrated—NH₂ SPE column (2 g), the solution was then concentrated in vacuo togive the desired product (36 mg) as an off white solid.

LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=390.

Example 317:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A solution of methyl2-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinate(for a preparation see Intermediate 242, 400 mg, 0.989 mmol), calciumchloride (220 mg, 1.978 mmol) and NaBH₄ (748 mg, 19.78 mmol) intetrahydrofuran (5 mL) and ethanol (2.5 mL) was stirred under nitrogenat 65° C. for 1 h. The reaction mixture was concentrated in vacuo andpartitioned between ethyl acetate (8 mL) and water (8 mL). The organiclayer was further washed with water (2×8 mL) and concentrated in vacuoto give the crude product (400 mg). The crude product was dissolved in1:1 MeOH:DMSO (2×3 mL) and purified by MDAP (HpH). The appropriatefractions were combined and concentrated in vacuo to give the product(89 mg, 0.236 mmol, 24%). LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=377.

Example 318:(2S,3R,4R)-1-acetyl-4-((6-(2-aminoethoxy)pyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A mixture of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 80 mg, 0.296 mmol), sodiumtert-butoxide (59.8 mg, 0.622 mmol), Pd₂(dba)₃) (27.1 mg, 0.030 mmol),QPhos (21.12 mg, 0.030 mmol) and tert-butyl(2-((6-bromopyridin-2-yl)oxy)ethyl)carbamate (for a preparation seeIntermediate 245, 94 mg, 0.296 mmol) in anhydrous toluene (1 mL) wasstirred under nitrogen at 70° C. for 15 h. The reaction mixture wasdiluted with EtOAc (5 mL) and filtered through a Celite cartridge. Thecartridge was washed with EtOAc (15 mL) and the filtrate evaporated invacuo. The residue was dissolved in MeOH (2 mL) and applied to aMeOH-preconditioned SCX-2 cartridge (2 g). The cartridge was washed withMeOH (12 mL), followed by 2 M NH₃/MeOH (12 mL). The basic wash wasevaporated in vacuo and the residue dissolved in anhydrous 1,4-dioxane(0.5 mL). The solution was treated with 4 M HCl in 1,4-dioxane (0.5 mL,16.46 mmol) and left to stand in a stoppered vessel for 1 h. Thereaction mixture was evaporated in vacuo and the residue purified byMDAP (HpH). The appropriate fractions were combined and the solventremoved by rotary evaporation to give the title compound as a lightbrown solid (46 mg, 0.113 mmol, 38%). LCMS (2 min Formic): Rt=0.72 min,[MH]⁺=406.

Example 319:N-(2-((6-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2-yl)oxy)ethyl)acetamide

To(2S,3R,4R)-1-acetyl-4-((6-(2-aminoethoxy)pyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Example 318, 30 mg, 0.074 mmol) and pyridine (12μL, 0.148 mmol) in DCM (0.25 mL) was added acetyl chloride (0.023 mL,0.327 mmol) and the mixture stirred in a stoppered vessel at rt for 1.5h. Further acetyl chloride (4 μL) was added and the mixture stirred in astoppered vessel at rt for 1.5 h. The reaction mixture was evaporatedunder a stream of nitrogen and the residue was purified by MDAP(Formic). The appropriate fractions were combined and the solventevaporated in vacuo to give the title compound as an off-white solid (22mg, 0.049 mmol, 66%). LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=448.

Example 320:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)phenyl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

To a solution of(2S,3R,4R)-1-acetyl-4-((3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 239, 66.1 mg, 0.135 mmol) intetrahydrofuran (1.5 mL), was added 1M TBAF in THF (0.675 mL, 0.675mmol) and the reaction stirred under nitrogen for 1 h. The reaction wasthen concentrated and the sample was redissolved in 1:1 MeOH:DMSO (1 mL)and purified by MDAP (Formic). The solvent was concentrated to give therequired product (25.2 mg, 0.067 mmol, 50%) as a colourless oil. LCMS (2min Formic): Rt=0.96 min, [MH]⁺=376.

Example 321:(2S,3R,4R)-1-acetyl-4-((2-aminophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

To a suspension of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((2-nitrophenyl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 246, 90 mg, 0.231 mmol) inisopropanol (11 mL) under a nitrogen atmosphere was added iron powder(154 mg, 2.77 mmol) and ammonium chloride (1.233 mg, 0.023 mmol). Theflask was heated to 100° C. and stirred for 2 h. Further ammoniumchloride (1.233 mg, 0.023 mmol) was added and the reaction heated to115° C. for 2 h. The heat on the reaction was reduced to 105° C. and thereaction allowed to stir at this temperature for 16 h. The reactionmixture was diluted with MeOH and filtered. The residue was washed withfurther MeOH (2×20 mL) and the combined filtrates concentrated in vacuo,to afford a brown residue. This was taken up in DCM and added to a SNAPsilica cartridge (10 g) and was purified by flash chromatography on aBiotage SP4, eluting with 0->60% EtOAc/cyclohexane. The appropriatefractions were collected and concentrated in vacuo to afford the desiredproduct as a beige solid (69 mg, 0.191 mmol, 83%). LCMS (2 min Formic):Rt=1.04 min, [MH]⁺=361.

Example 322:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(2-hydroxyethoxy)phenyl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A solution of(2S,3R,4R)-1-acetyl-4-((3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 249, 231 mg, 0.444 mmol) inanhydrous THF (1 mL) was treated with TBAF (1 M solution in THF) (2.0mL, 2.000 mmol) and the mixture allowed to stand at rt for 45 min. Thereaction mixture was evaporated in vacuo and the residue purified byMDAP (HpH). The appropriate fractions were combined and the solventremoved by rotary evaporation to give the desired product which wasstill impure. This was loaded in DCM (1 mL) and purified on a silicacartridge (25 g) using a gradient of 0-15% MeOH in DCM over 10 CV. Theappropriate fractions were combined and the solvent evaporated in vacuoto give the desired product which was still impure. This was furtherpurified by MDAP (Formic). The appropriate fractions were combined andthe solvent removed by rotary evaporation to give the title compound asa white foam (91 mg, 0.224 mmol, 51%).

LCMS (2 min Formic): Rt=0.95 min, [MH]⁺=406.

Example 323:(2S,3R,4R)-1-acetyl-4-((3-(2-aminoethoxy)phenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A solution of tert-butyl(2-(3-(((2S,3R,4R)-1-acetyl-6-cyano-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenoxy)ethyl)carbamate(for a preparation see Intermediate 251, 123 mg, 0.244 mmol) in1,4-dioxane (0.5 mL) was treated with 4 M HCl in 1,4-dioxane (1 mL, 4.00mmol) and the mixture left to stand in a stoppered vessel for 16 h. Thereaction mixture was evaporated in vacuo and the gum purified by MDAP(HpH). The appropriate fractions were combined and the solventevaporated in vacuo to give the title compound as a light brown solid(49 mg, 0.121 mmol, 50%). LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=405.

Example 324:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4-(hydroxymethyl)pyrimidin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

(2S,3R,4R)-1-Acetyl-4-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 254, 30 mg, 0.061 mmol) was taken upin 1M TBAF in THE (1 mL, 1.00 mmol) and allowed to stir at rt for 1 h.The reaction was concentrated and purified using a SP4 SNAP silica (10g) column, eluting with 0-100% EtOAc:cyclohexane—nothing UV active wascollected. The column was run again, eluting with 0-10% 2MNH₃/MeOH:DCM—nothing UV active was collected. The waste column eluentwas concentrated to an orange gum which was purified by MDAP (Formic).One fraction was collected which was concentrated and dried to give theproduct (2 mg, 5.30 μmol, 9%), as a colourless gum.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=378.

Example 325:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-isopropylpyrimidin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

A mixture of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 231, 80 mg, 0.297 mmol), 18-crown-6(38 mg, 0.144 mmol), potassium fluoride (26 mg, 0.448 mmol) and2-chloro-5-isopropylpyrimidine (52 mg, 0.332 mmol) was suspended inanhydrous DMSO (5 mL) and treated with DIPEA (0.086 mL, 0.495 mmol). Themixture was stirred under nitrogen at 140° C. for 16 h. The reaction wasallowed to cool to rt and purified by formic MDAP. The appropriatefractions were evaporated under a stream of nitrogen to give the desiredproduct as a yellow solid. LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=390.

Example 326:(2S,3R,4R)-1-acetyl-4-((5-chloro-6-(hydroxymethyl)pyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

To a solution of(2S,3R,4R)-1-acetyl-4-((6-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloropyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 258, 60 mg, 0.114 mmol) intetrahydrofuran (1 mL), was added TBAF (0.571 mL, 0.571 mmol, 1M in THF)and the reaction allowed to stir under nitrogen at rt for 2 h. Thereaction was concentrated and partitioned between EtOAc and water. Theaqueous layer was further extracted with EtOAc and the organic layerscombined, washed with water and dried over a hydrophobic frit. Thesample was concentrated and loaded in dichloromethane and purified byflash chromatography on SP4 silica (10 g) using 10-50%EtOAc/dichloromethane over 10CV. The appropriate fractions were combinedand concentrated to give the product (36 mg, 0.088 mmol, 77%) as acolourless oil. LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=411.

Example 327:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

A solution of (2S,3R,4R)-ethyl1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 225, 515 mg, 1.628 mmol), DavePhos(64.1 mg, 0.163 mmol), 2-bromo-5-fluoropyridine (344 mg, 1.953 mmol),Pd₂(dba)₃ (74.5 mg, 0.081 mmol) and sodium tert-butoxide (469 mg, 4.88mmol) in 1,4-dioxane (30 mL) was stirred under nitrogen at 90° C. for 1h. The reaction mixture was cooled to rt and then filtered throughcelite and the celite washed with ethyl acetate (50 mL). The combinedfiltrates were concentrated in vacuo and taken up in EtOAc (75 mL) andsaturated sodium bicarbonate solution (20 mL). The product entered theaqueous layer and the organic layer was discarded. The aqueous layer wasacidified to pH2 with 2M hydrochloric acid (10 mL) and evaporated invacuo. The crude product was added to a silica gel column and was elutedwith 0-20% 2M NH₃ in methanol/DCM. The desired fractions were combinedand concentrated to give the product (45 mg, 0.117 mmol, 7%).

LCMS (2 min Formic): Rt=0.80 min, [MH]⁺=384.

The following example was prepared in a similar manner to Example 327using Pd₂(dba)₃, DavePhos and NaOtBu to couple the appropriate arylhalide to Intermediate 261.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)328 (2S,3R,4R)-1- acetyl-2-ethyl-4- ((5-fluoropyridin- 2-yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxylic acid, TFA salt

310 37 372 0.64 (2 min TFA)

Example 329:(2S,3R,4R)-1-acetyl-4-((4-cyano-3-methylphenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-ethyl1-acetyl-4-((4-cyano-3-methylphenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 262, 200 mg, 0.463 mmol) wasdissolved in 1,4-dioxane (2 mL). Water (2.0 mL) was added followed byLiOH (22.20 mg, 0.927 mmol) and reaction mixture stirred at rt for ˜3 h.The dioxane was removed in vacuo and acetic acid (0.053 mL, 0.927 mmol)was added. The reaction mixture was partitioned between DCM and water.The organic layer was separated and the aqueous layer extracted with DCM(3×30 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated to give the product (153 mg, 0.379 mmol, 82%) as a paleorange solid. LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=404.

The following examples were prepared in a similar manner to Example 329using Pd₂(dba)₃, QPhos and Cs₂CO₃ to couple the appropriate aryl halideto Intermediate 225 (2-cPr) or 263 (2-Et); followed by hydrolysis withLiOH.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)330 (2S,3R,4R)-1- acetyl-4-((4-cyano- 3- fluorophenyl)amino)-2-cyclopropyl- 3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxylic acid

105 96 406 ([M − H]⁻) 0.95 (2 min Formic) 331 (2S,3R,4R)-1-acetyl-4-((4- cyanophenyl)amino)- 2-ethyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxylic acid

92 92 378 0.89 (2 min Formic) 332 (2S,3R,4)-1-acetyl- 2-cyclopropyl-3-methyl-4-((4- (methylsulfonyl) phenyl)amino)- 1,2,3,4-tetrahydroquinoline- 6-carboxylic acid

54 92 441 0.63 (2 min HpH) 333 (2S,3R,4R)-1- acetyl-4-((4-chloropyridin-2- yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxylic acid

49 79 400 0.82 (2 min Formic) 334 (2S,3R,4R)-1- acetyl-4-((4-cyano- 2-methoxyphenyl) amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxylic acid

43 100 420 0.99 (2 min Formic)

Example 335:(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid

(2S,3R,4R)-Ethyl-1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylate(for a preparation see Intermediate 263, 439 mg, 1.107 mmol) was takenup in tetrahydrofuran (THF) (5 mL) and water (5.00 mL). Lithiumhydroxide (66.3 mg, 2.77 mmol) was added and the reaction stirred for ˜2h at rt. 2M HCl(aq) (1.384 mL, 2.77 mmol) was added followed by 10%MeOH/DCM and water. The biphasic mixture was stirred for 5 min and thelayers then separated. The aqueous layer was further extracted with 10%MeOH/DCM. After four washes the combined organics were collected, dried(Na₂SO₄) and concentrated in vacuo to afford the desired product as ayellow solid (375.2 mg, 1.018 mmol, 92%).

LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=369.

The following examples were prepared in a similar manner to Example 335using KF, 18-crown-6 and DIPEA to couple the appropriate aryl halidewith Intermediate 225; followed by hydrolysis with LiOH.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)336 (2S,3R,4R)-1- acetyl-2- cyclopropyl-3- methyl-4- (pyrimidin-2-ylamino)-1,2,3,4- tetrahydroquinoline- 6-carboxylic acid

775 100 367 0.74 (2 min Formic)

Example 337:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)phenyl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)phenyl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Example 320, 20.2 mg, 0.054 mmol) and potassiumcarbonate (14.87 mg, 0.108 mmol) in dimethyl sulfoxide (DMSO) (3 mL),was added hydrogen peroxide (0.047 mL, 0.538 mmol) and the reactionstirred under nitrogen for 1 h. The reaction was quenched with 10%sodium thiosulfate (40 mL) and extracted with DCM (2×40 mL). The organicextracts were combined and washed with water. The extracts were thendried over a hydrophobic frit and concentrated in vacuo. The sample wasloaded in dichloromethane and purified by chromatography on silica 10 gusing a 0-10% methanol-dichloromethane over 25 CV. The appropriatefractions were combined and concentrated to give the required product(19.8 mg, 0.050 mmol, 94%) as an off-white solid. LCMS (2 min Formic):Rt=0.76 min, [MH]⁺=394.

The following Examples were prepared in a similar manner to Example 337by hydrolysis of Examples 300, 323 & 322 using H₂O₂.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)338 (2S,3R,4R)-1-acetyl- 4-((5-chloro-4- methylpyrimidin-2- yl)amino)-2-cyclopropyl-3- methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

12 40 414 0.91 (2 min HpH) 339 (2S,3R,4R)-1-acetyl- 4-((3-(2-aminoethoxy)phenyl) amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

22 62 423 0.76 (2 min HpH) 340 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((3-(2- hydroxyethoxy) phenyl)amino)-3- methyl-1,2,3,4- tetrahydroquinoline-6-carboxamide

50 74 424 0.78 (2 min HpH)

Example 341:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 264, 188 mg, 0.516 mmol,) in a roundbottom flask hydrogen peroxide (0.444 mL, 5.16 mmol), potassiumcarbonate (143 mg, 1.032 mmol) and dimethyl sulfoxide (DMSO) (3.5 mL)were added. The reaction mixture was stirred at rt for 1 h and wasquenched with sodium thiosulphate, diluted with DCM and washed withwater. The organic layer was dried, concentrated in vacuo and purifiedby silica gel column chromatography eluting with a gradient ofcyclohexane/ethyl acetate (20%-85%). The cartridge was then flushed with90% ethyl acetate in cyclohexane to give title compound (137 mg, 63%)LCMS (2 min Formic): Rt=0.69 min [MH]⁺=383.

The following examples were prepared in a similar manner to Example 341using Pd(QPhos)₂ and NaOtBu or Cs₂CO₃ to couple the appropriate arylhalide with Intermediate 231; followed by hydrolysis with H₂O₂.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)342 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((3- methoxypyridin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline- 6-carboxamide

80 45 395 0.56 (2 min Formic) 343 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((4- methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

44 33 356 0.78 (2 min Formic) 344 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((6- methylpyridin-3- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

127 82 379 0.54 (2 min Formic) 345 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((5- methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

50 40 379 0.55 (2 min Formic) 346 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((3- methylpyridin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

116 97 379 0.54 (2 min Formic) 347 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((6- (morpholinomethyl) pyridin-2-yl)amino)- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

18 91 464 0.58 (2 min Formic) 348 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5- methoxy-4- methylpyrimidin-2- yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

41 50 410 0.81 (2 min HpH) 349 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((5-methoxypyridin-2- yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide

26 34 377 0.69 (2 min Formic)

The following Examples (350-352) were prepared in a similar manner toExample 341 using PdQPhos)₂ and NaOtBu or Cs₂CO₃ to couple theappropriate protected aryl halde with Intermediate 231; followed byhydrolysis with H₂O₂; followed by a deprotection step as detailed below:

Example 350:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of(2S,3R,4R)-1-acetyl-4-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(102 mg, 0.201 mmol) in anhyrous THE (0.5 mL) was treated with TBAF (1Msolution in THF) (1.0 mL, 1.0 mmol) and the mixture allowed to stand atrt for 45 min. The reaction mixture was evaporated in vacuo and theresidue purified by MDAP (HpH) to give crude title compound as a whitesolid. This solid was dissolved in MeOH and applied to a 1 gMeOH-preconditioned SCX-2 cartridge. The cartridge was washed with MeOH(6 mL) followed by 2M NH₃ in MeOH and the basic wash evaporated under astream of nitrogen to give title compound as a white solid (39 mg, 0.099mmol, 49%).

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=395.

Example 351:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-(piperazin-1-ylmethyl)pyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

In a 50 mL RB flask, 4M HCl in 1,4-dioxane (0.533 mL, 2.133 mmol) wasadded to a stirred solution of tert-butyl4-((6-(((2S,3R,4R)-1-acetyl-6-carbamoyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2-yl)methyl)piperazine-1-carboxylate(40 mg, 0.071 mmol) in 1,4-dioxane (3 mL). The resulting solution wasleft stirring for 1.5 h at rt. Volatiles were removed under reducepressure to afford a yellow gum. This gum was dissolved in MeOH andloaded on a 5 g SCX cartridge, washed with methanol (3 CV) and flushedwith MeOH/NH3 (2M, 3CV). Ammonia fractions were combined and volatilesremoved under reduce pressure to afford 27.8 mg of yellow gum. Thecompound was purified my MDAP (Formic). The compound was not collected,so the waste fraction was filtered through a SCX cartridge, and elutedwith 2M NH₃ in MeOH solution. The appropriate fraction was evaporated invacuo to give title compound (31.7 mg, 0.069 mmol, 96%)

LCMS (2 min Formic): Rt=0.47 min, [MH]⁺=463.

Example 352:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((3-(piperazin-1-yl)phenyl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

Trifluoroacetic acid (0.5 ml, 6.49 mmol) was added to tert-butyl4-(3-(((2S,3R,4R)-1-acetyl-6-carbamoyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)piperazine-1-carboxylate(41 mg, 0.075 mmol) and stirred at rt for 0.5 h. The solvent wasevaporated in vacuo to give a colourless residue. The residue was loadedin methanol and purified by SPE on sulphonic acid (SCX) 2 g usingsequential solvents of MeOH, NH3 in MeOH (2M). The appropriate fractionswere combined and evaporated in vacuo to give the required product as acolourless oil (31 mg). The sample was dissolved in 1:1 MeOH:DMSO (1 mL)and purified MDAP (HpH). The solvent was evaporated in vacuo to give therequired product 11.2 mg.

LCMS (2 min HpH): Rt=0.74 min, [MH]⁺=448.

Example 353:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4-fluorophenyl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4-fluorophenyl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Example 302, 54 mg, 0.149 mmol) in dimethylsulfoxide (DMSO) (2 mL) was added hydrogen peroxide (0.130 mL, 1.486mmol) and potassium carbonate (41.1 mg, 0.297 mmol) and reaction mixturewas stirred at rt. The reaction mixture was quenched with sat. sodiumthiosulfate solution and partitioned between DCM and water. The organiclayer was separated and aq. layer re-extracted with DCM. Combinedorganic layers were dried (Na₂SO₄) and concentrated to give a crudeyellow oil. This was purified by silica gel column chromatography onSiO₂ eluting with 0-100% ethyl acetate/cyclohexane to give the product(50 mg, 0.131 mmol, 88%) as a colourless oil. LCMS (2 min Formic):Rt=0.92 min, [MH]⁺=382.

The following examples were prepared in a similar manner to Example 353using Pd₂(dba)₃ DavePhos and NaOtBu to couple the appropriate arylhalide with Intermediate 231; followed by hydrolysis with H₂O₂.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)354 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4- ((3,4- difluorophenyl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

47 53 271 ([M − NHAr]⁺) 0.95 (2 min Formic) 355 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4- ((2,4- difluorophenyl) amino)-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

 7 99 400 0.96 (2 min Formic) 356 (2S,3R,4R)-1-acetyl- 4-((4-chlorophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

63 68 398 1.00 (2 min Formic) 357 (2S,3R,4R)-1-acetyl- 4-((3-chlorophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

18 85 271 ([M − NHAr]⁺) 0.99 (2 min Formic) 358 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6- (methoxymethyl) pyridin-2-yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

12 33 409 0.59 (2 min Formic) 359 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3- fluorophenyl)amino)- 3-methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

38 85 382 0.93 (2 min Formic) 360 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3- methoxyphenyl) amino)-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

73 56 394 0.89 (2 min Formic) 361 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4- methoxyphenyl) amino)-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

23 55 394 0.88 (2 min Formic) 362 (2S,3R,4R)-1-acetyl- 4-((3-chloro-4-cyanophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

 7 31 423 0.91 (2 min Formic) 363 (2S,3R,4R)-1-acetyl- 4-((4-chloro-3-methoxyphenyl) amino)-2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

35 15 428 0.97 (2 min Formic) 364 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((2- methoxyphenyl) amino)-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

18 57 394 0.95 (2 min Formic) 365 (2S,3R,4R)-1-acetyl- 4-((4-chloro-2-methoxyphenyl) amino)-2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

22 90 428 1.04 (2 min Formic)

The following examples (366-369) were prepared in a similar manner toExample 352 using Pd₂(dba)₃ DavePhos and NaOtBu or Cs₂CO₃ to couple theappropriate protected aryl halde with Intermediate 231; followed byhydrolysis with H₂O₂; followed by deprotection as detailed below:

Example 366:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(piperazin-1-yl)phenyl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

4M hydrogen chloride in dioxane (1.014 mL, 4.05 mmol) was added totert-butyl4-(4-(((2S,3R,4R)-1-acetyl-6-carbamoyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)piperazine-1-carboxylate(69.4 mg, 0.101 mmol) and stirred at rt for 4 h. The solvent was removedin vacuo to give an orange residue. The residue purified by MDAP (HpH)to give the title compound as a yellow solid (18 mg, 40%). LCMS (2 minFormic): Rt=0.60 min, [MH]⁺=448.

Example 367:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-(rac-1-hydroxyethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-4-((6-(1-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(94 mg, 0.180 mmol) in tetrahydrofuran (THF) (1.5 mL) was added TBAF (1Min THF) (0.899 mL, 0.899 mmol) and the reaction allowed to stir undernitrogen for 1 h. The reaction was concentrated, partitioned betweenEtOAc and water and the aqueous layer further extracted with EtOAc. Theorganic layers were combined, dried over a hydrophobic frit andconcentrated. The residue was purified by column chromatography elutingwith a gradient of 10-50% methanol-dichloromethane to give the product(59.8 mg, 0.146 mmol, 81%) as a colourless oil. LCMS (2 min Formic):Rt=0.54 min, [MH]⁺=409.

Example 368a & 368b:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-(S-1-hydroxyethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(386a) &(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-(R-1-hydroxyethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(386b)

(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-(rac-1-hydroxyethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Example 367, ˜45 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 300×20 mm ChiralpakAD-H column eluting with 15% ethanol in 80% hexane at a flow rate of 20mL/min. Peak 1/Enantiomer A fractions were collected between 20 and 23.5min. Peak 2/Enantiomer B fractions were collected between 25.5 and 30min. Fraction solutions were combined then evaporated to dryness to giveEnantiomer A (22 mg) and Enantiomer B (25 mg) as white solids.

Enantiomer A

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 15% ethanol in heptane at 1 mL/min—Rt=11 min. >99% ee by UV.

Enantiomer B

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AD-H column elutingwith 15% ethanol in heptane at 1 mL/min—Rt=13 min, 94% ee by UV.

Example 369:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((2-(piperazin-1-yl)phenyl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

Hydrogen chloride (1.186 mL, 4.74 mmol) in 1,4-dioxane (0.5 mL) wasadded to tert-butyl4-(2-(((2S,3R,4R)-1-acetyl-6-carbamoyl-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)piperazine-1-carboxylate(81.2 mg, 0.119 mmol) and stirred at rt for 1.5 h. The solvent wasevaporated in vacuo to give a yellow residue. The residue was purifiedby MDAP (Formic). The sample was loaded in methanol and purified by SPEon sulphonic acid (SCX) 1 g using sequential solvents of methanol, 2Mammonia/methanol. The appropriate fractions were combined and evaporatedin vacuo to give a crude yellow oil. This crude was further purifiedusing a MDAP (HpH) to give title compound as a white solid (8 mg, 14%).LCMS (2 min Formic): Rt=0.65 min, [MH]⁺=448.

Example 370:(2S,3R,4R)-1-acetyl-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-4-((5-fluoropyridin-2-yl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 268, 64 mg, 0.179 mmol) inN,N-dimethylformamide (DMF) (1 mL) was added HATU (102 mg, 0.269 mmol)followed by ammonium chloride (20 mg ml, 0.374 mmol) and DIPEA (0.125ml, 0.716 mmol). The resulting reaction mixture was stirred at rt underN₂ for 16 h. The crude reaction mixture was purified directly by MDAP(TFA) the fractions containing product were extracted with DCM. The pHof the aqueous layer was adjusted to ˜pH9. The aqueous layer was thenextracted with ethyl acetate (100 mL). The combined organic layers weredried (Na₂SO₄) and concentrated to give the title compound as a whitesolid (23 mg, 27%). LCMS (2 min TFA): Rt=0.53 min, [MH]⁺=357.

The following examples were prepared in a similar manner to Example 370using Pd₂(dba)₃ DavePhos and NaOtBu or Cs₂CO₃ to couple the appropriatearyl halide with Intermediate 225 (2-cPr) or 261 (2-Et); followed byamide formation with HATU, DIPEA and NH₄Cl.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)371 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3- methyl-4-((6- methylpyridin-2-yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

26 43 379 0.55 (2 min HpH) 372 (2S,3R,4R)-1-acetyl- 2-ethyl-4-((5-fluoropyridin-2- yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide

11 14 371 0.56 (2 min TFA) 373 (2S,3R,4R)-1-acetyl- 4-((4-cyano-2-fluorophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

11 16 407 0.88 (2 min Formic) 374 (2S,3R,4R)-1-acetyl- 4-((4-cyano-3-methoxyphenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

20 34 419 0.85 (2 min Formic) 375 (2S,3R,4R)-1-acetyl- 4-((4-cyano-3-hydroxyphenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

 9 18 403 0.76 (2 min Formic)

Example 376:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 271, 22 mg, 0.060 mmol) andHATU (27.5 mg, 0.072 mmol) in N,N-dimethylformamide (2 mL) was addedammonium chloride (6.44 mg, 0.120 mmol) followed by DIPEA (0.042 mL,0.241 mmol). The reaction mixture was stirred at for 2 h. The volatileswere removed under reduced pressure and the resulting crude was purifiedby MDAP (Formic) to give title compound as a white powder. (11 mg, 0.030mmol, 50%).

LCMS (2 min Formic): Rt=0.52 min [MH]⁺=365.

The following examples were prepared in a similar manner to Example 376using PdQPhos₂ and NaOtBu or Cs₂CO₃ to couple the appropriate arylhalide with Intermediate 225 (2-cPr), 261 (2-Et) or 267 (2-Me); followedby hydrolysis with LiOH; followed by amide formation with HATU, DIPEAand NH₄Cl.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)377 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((5- fluoro-6- methylpyridin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline- 6-carboxamide

105  77 397 0.70 (2 min Formic) 378 (2S,3R,4R)-1-acetyl- 4-((4-cyanophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

72 40 389 0.84 (2 min Formic) 379 (2S,3R,4R)-1-acetyl-4-((5-chloropyridin- 2-yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

198  80 399 0.81 (2 min Formic) 380 (2S,3R,4R)-1-acetyl-2-cyclopropyl-3- methyl-4-((5- methylpyrazin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

35 35 380 0.69 (2 min Formic) 381 (2S,3R,4R)-1-acetyl- 4-((4-cyano-3-fluorophenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

54 56 407 0.88 (2 min Formic) 382 (2S,3R,4R)-1-acetyl- 4-((4-cyano-3-methylphenyl)amino)- 2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

 7  6 271 [M − NHAr]⁺ 0.88 (2 min Formic) 383 (2S,3R,4R)-1-acetyl-4-((4- cyanophenyl)amino)- 2-ethyl-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

56 66 377 0.81 (2 min Formic) 384 (2S,3R,4R)-1-acetyl- 4-((4-cyanophenyl)amino)- 2,3-dimethyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide

43 43 363 0.78 (2 min Formic) 385 (2S,3R,4R)-1-acetyl-4-((6-cyanopyridin- 3-yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

 4  6 390 0.75 (2 min Formic) 386 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4- methoxypyrimidin- 2-yl)amino)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

16 82 396 0.58 (2 min Formic) 387 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4- (dimethylamino) pyrimidin-2-yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

33 36 409 0.59 (2 min Formic) 388 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((4- (methylsulfonyl) phenyl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

47 88 442 0.75 (2 min Formic) 389 (2S,3R,4R)-1-acetyl-4-((4-chloropyridin- 2-yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

29 59 399 0.72 (2 min Formic) 390 (2S,3R,4R)-1-acetyl- 4-((4-cyano-2-methoxyphenyl) amino)-2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

29 67 419 0.90 (2 min Formic) 391 (2S,3R,4R)-1-acetyl- 4-((5-chloro-6-cyanopyridin-3- yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

24 75 422 0.88 (2 min Formic) 392 (2S,3R,4R)-1-acetyl- 4-((2-cyano-4-methoxyphenyl) amino)-2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

 6 63 419 0.91 (2 min Formic) 393 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6- methoxypyridin-2- yl)amino)-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

57 85 423 1.17 (2 min Formic) 394 (2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((6- methylpyridin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

 2 10 353 0.46 (2 min Formic)

Example 395:(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 335, 75 mg, 0.204 mmol) inN,N-dimethylformamide (DMF) (2 ml) was added HATU (116 mg, 0.305 mmol)followed by DIPEA (0.107 ml, 0.611 mmol). The resulting reaction mixturewas stirred at rt under N₂ for 15 min Ammonium chloride (10.89 mg, 0.204mmol) was then added and the reaction stirred for ˜1 h. The reactionmixture was quenched by the addition of water. Et₂O was added and thelayers separated. The aqueous layer was further extracted with Et₂O. Thecombined organics were then back extracted with H₂O. The aqueous layerwas further extracted with DCM and the combined Et₂O/DCM organics dried(hydrophobic frit) and concentrated in vacuo to afford the crudeproduct. The crude product was taken up in DCM and purified by silicagel column chromatography eluting with 0-40% (20% MeOH/DCM) to give theproduct (51.8 mg, 0.141 mmol, 69%) as a colourless gum.

LCMS (2 mi Formic): Rt=0.61 m [MH]=368.

The following examples were prepared in a similar manner to Example 395using KF, 18-crown-6 and DIPEA to couple the appropriate aryl halidewith Intermediate 225 (2-cPr) or 267 (2-Me); followed by hydrolysis withLiOH; followed b amide formation with HATU, DIPEA and NH₄Cl.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)396 (2S,3R,4R)-1-acetyl- 2,3-dimethyl-4-((4- methylpyrimidin-2-yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

40 80 354 0.56 (2 min Formic) 397 (2R,3S,4S)-1-acetyl- 2-cyclopropyl-3-methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide*

20 14 380 0.65 (2 min Formic) *After chiral HPLC separation of theracemate using a 250 × 30 mm Chiralcel OD-H column eluting with 15%ethanol in heptane. This (2^(nd) eluting) isomer eluted at t = 12.5-16min.

Example 398:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 273, 110 mg, 0.300 mmol),ammonium chloride (48.2 mg, 0.901 mmol), HATU (148 mg, 0.390 mmol) andDIPEA (0.210 mL, 1.201 mmol) was stirred in a closed vessel at rt for 45min. The solution was purified directly by MDAP (HpH) to give theproduct (65 mg, 0.178 mmol, 59%).

LCMS (2 min Formic): Rt=0.65 min, [MH]⁺=366.

The following examples were prepared in a similar manner to Example 398using KF, 18-crown-6 and DIPEA to couple the appropriate aryl halidewith Intermediate 225; followed by hydrolysis with LiOH; followed byamide formation with HATU, DIPEA and NH₄Cl.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)399 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3- methyl-4-(pyrimidin-2-ylamino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

852 49 366 0.65 (2 min Formic) 400 (2S,3R,4R)-1-acetyl-4-((5-cyanopyridin- 2-yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

 86 56 390 0.77 (2 min Formic)

Example 401:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-(trifluoromethyl)pyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

2-chloro-4-(trifluoromethyl)pyrimidine (191 mg, 1.044 mmol), potassiumfluoride (91 mg, 1.566 mmol) and 18-crown-6 (138 mg, 0.522 mmol) wereadded to a 2 mL microwave vial in DMSO (1 mL).(2S,3R,4R)-1-Acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 276, 100 mg, 0.348 mmol) and DIPEA(0.304 mL, 1.740 mmol) were added and reaction mixture was heated at160° C. for 4 h. The reaction mixture partitioned between ethyl acetateand sat. LiCl solution. The organic layer was separated, washed withwater, dried (Na₂SO₄) and concentrated to give a crude brown residue.This was purified by silica gel column chromatography eluting with 0-10%methanol/DCM to give the product (134 mg, 0.309 mmol, 89%) as a brownoil. LCMS (2 mm Formic): Rt=0.85 min [MH]⁺=434.

The following examples were prepared in a similar manner to Example 401using KF, 18-crown-6 and DIPEA to couple the appropriate aryl halidewith Intermediate 276.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)402 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((5- fluoropyrimidin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline- 6-carboxamide

110  82 384 0.75 (2 min Formic) 403 (2S,3R,4R)-1-acetyl- 4-((5-chloropyrimidin-2- yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

91 65 400 0.82 (2 min Formic) 404 (2S,3R,4R)-1-acetyl- 4-((5-cyanopyrimidin-2- yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

30 22 391 0.73 (2 min Formic) 405 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((5- methylpyrimidin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

 4  3 380 0.69 (2 min Formic) 406 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((4,5- dimethylpyrimidin- 2-yl)amino)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

37 13 394 0.81 (2 min HpH) 407 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((4-ethylpyrimidin-2- yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide

53 22 394 0.72 (2 min Formic) 408 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((4,6- dimethylpyrimidin- 2-yl)amino)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

87 31 394 0.82 (2 min HpH) 409 (2S,3R,4R)-1-acetyl- 4-((5-cyano-6-methylpyridin-2- yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

158  56 404 0.83 (2 min Formic) 410 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5- fluoro-4- methylpyrimidin-2- yl)amino)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

100  48 398 0.80 (2 min Formic) 411 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4- isopropylpyrimidin- 2-yl)amino)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

67 32 408 0.80 (2 min Formic) 412 (2S,3R,4R)-1-acetyl- 4-((5-cyano-4-methylpyrimidin-2- yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

46 22 405 0.77 (2 min Formic) 413 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((4- (3,6-dihydro-2H- pyran-4- yl)pyrimidin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline- 6-carboxamide

15  6 448 0.79 (2 min Formic)

Example 414:(2S,3R,4R)-1-acetyl-4-((3-cyanopyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of(2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 276, 60 mg, 0.209 mmol),2-fluoronicotinonitrile (51.0 mg, 0.418 mmol) and triethylamine (0.058mL, 0.418 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was stirred in aclosed vessel in a microwave at 200° C. for 1 h. The reaction mixturewas purified directly by MDAP (Formic) to give a partial formic salt sothe material was dissolved in MeOH and applied to a 2 g NH₂ cartridgewhich had been pre-equilibrated with MeOH (2 mL). The cartridge waswashed with MeOH (2 mL) and this solution was concentrated in vacuo togive the product (25 mg, 0.064 mmol, 31% yield). LCMS (2 min Formic):Rt=0.79 min, [MH]⁺=390.

The following example was prepared in a similar manner to Example 414using NEt₃ in NMP to couple the appropriate aryl halide withIntermediate 276.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)415 (2S,3R,4R)-1-acetyl- 4-((5- cyanopyrimidin-2- yl)amino)-2-cyclopropyl-3- methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

100 74 391 0.74 (2 min Formic)

Example 416:(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To(2S,3S,4R)-2-cyclopropyl-3-methyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 280, 72 mg, 0.204 mmol) in a roundbottom flask pyridine (0.049 mL, 0.613 mmol), acetyl chloride (0.029 mL,0.409 mmol) and anhydrous dichloromethane (DCM) (4 mL) were added. Thereaction mixture was stirred at rt under nitrogen for 16 h. To thereaction mixture pyridine (0.050 mL, 0.613 mmol), acetyl chloride (0.029mL, 0.409 mmol) and chloroform (2 mL) were added. The reaction mixturewas stirred at 60° C. under nitrogen for 1 h 30 min. The reactionmixture was cooled, concentrated in vacuo and purified by MDAP (Formic)to give title compound as a white solid (6 mg, 6%).

LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=395.

Example 417:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a stirred mixture of(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)pyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 282, 83 mg, 0.220 mmol) andpotassium carbonate (60.9 mg, 0.441 mmol) in DMSO (0.75 mL) was addedhydrogen peroxide (35 wt % in water) (0.045 mL, 0.514 mmol). The mixturewas stirred in a stoppered vessel at rt for 5 h. The reaction mixturewas diluted with water and extracted with DCM. The organic extracts werecombined and dried through a hydrophobic frit. The residue was purifiedby MDAP (HpH) to give title compound as a white solid (49 mg, 0.124mmol, 56%).

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=395.

Example 418:(2S,3R,4R)-1-acetyl-4-((3-carbamoylpyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a stirred mixture of(2S,3R,4R)-1-acetyl-4-((3-cyanopyridin-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Example 311, 81 mg, 0.218 mmol) and potassiumcarbonate (121 mg, 0.872 mmol) in DMSO (0.75 mL) was added hydrogenperoxide (35 wt % in water) (0.057 mL, 0.654 mmol). The reaction mixturewas diluted with water (2 mL) and a precipitate formed. The solid wasisolated by vacuum filtration, washed with water (10 mL) and dried in avacuum oven to give title compound as a white solid (68 mg, 0.167 mmol,77%).

LCMS (2 min Formic): Rt=0.60 min, [MH]⁺=408.

Example 419:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-hydroxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 357, 50 mg, 0.131 mmol) HATU (60.0mg, 0.158 mmol) and DIPEA (0.092 mL, 0.526 mmol) inN,N-dimethylformamide (DMF) (1 mL) was stirred at rt for 30 min.Hydroxylamine hydrochloride (18.27 mg, 0.263 mmol) was added and thereaction was stirred for a further 1 h. The solvent was removed underreduced pressure and the residue was purified by MDAP (HpH) to givetitle compound as a light brown solid (2 mg, 4%).

LCMS (2 min Formic): Rt=0.61 min, [MH]⁺=396.

Example 420:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)-6-methylpyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile

The(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((3-(hydroxymethyl)-6-methylpyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 285, 75 mg, 0.192 mmol) was taken upin dimethyl sulfoxide (DMSO) (2 mL) and was treated with potassiumcarbonate (53.1 mg, 0.384 mmol) and hydrogen peroxide (0.168 mL, 1.921mmol) and allowed to stir at rt for 1 h. Further hydrogen peroxide(0.168 mL, 1.921 mmol) was added and the reaction allowed to stir at rtfor 2 h. The reaction was diluted with sodium thiosulphate (aq) and wasextracted with EtOAc, the organic phase was dried using a hydrophobicfrit and concentrated to a oil. This oil was purified using a MDAP(Formic) and the appropriate fractions were summed and concentrated togive the product (11 mg, 0.027 mmol, 14%) as a white solid. LCMS (2 minFormic): Rt=0.55 min, [MH]⁺=409.

The following example was prepared in a similar manner to Example 420using NEt₃ in NMP to couple the Intermediate 228 with Intermediate 231;followed by deprotection with TBAF; followed by hydrolysis with H₂O₂.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)421 (2S,3R,4R)-1-acetyl- 4-((5-chloro-6- (hydroxymethyl)pyridin-2-yl)amino)-2- cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

19 72 429 0.74 (2 min Formic)

Example 422:(2S,3R,4R)-2-cyclopropyl-1-isobutyryl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-2-cyclopropyl-1-isobutyryl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carbonitrile(for a preparation see Intermediate 288, 5 mg, 0.013 mmol) in dimethylsulfoxide (DMSO) (2 mL), was added hydrogen peroxide (11.24 μl, 0.128mmol) and potassium carbonate (3.55 mg, 0.026 mmol) and the reactionallowed to stir at rt for 3 h. A further portion of hydrogen peroxide(11.24 μl, 0.128 mmol) was added and the reaction allowed to stir for 2h. Further hydrogen peroxide (100 μl, 1.142 mmol) and potassiumcarbonate (35.5 mg, 0.257 mmol) were added and the reaction stirred fora further 30 min. The reaction mixture was quenched with 10% sodiumthiosulfate and extracted twice with DCM. The organic extracts werecombined, washed with water, dried over a hyrdophobic frit andconcentrated in vacuo to give the product (3 mg, 7.36 μmol, 57%) as apale yellow oil. LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=408.

The following example was prepared in a similar manner to Example 422using propionyl chloride to acylate Intermediate 229, followed bydeprotection with TBAF; followed by the use of KF, 18-crown-6 and DIPEAto couple the appropriate aryl halide; followed by hydrolysis with H₂O₂.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)423 (2S,3R,4R)-2- cyclopropyl-3- methyl-4-((4- methylpyrimidin-2-yl)amino)-1- propionyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

9 86 394 0.73 (2 min Formic)

Example 424:(2S,3R,4R)-1-acetyl-4-((4-cyano-2-hydroxyphenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

(2S,3R,4R)-1-Acetyl-4-((4-cyano-2-methoxyphenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Example 390, 98 mg, 0.234 mmol) was suspended indichloromethane (DCM) (2 mL) and cooled to 0° C. in an ice bath. BBr₃(1M in DCM) (2.342 mL, 2.342 mmol) was added dropwise forming an orangesuspension and reaction mixture stirred at r. under N₂ for 1 h. Thereaction mixture was carefully poured onto ice-water and extracted withDCM. The organic layer was dried (Na₂SO₄) and concentrated to give 59 mgof crude orange oily solid. This was purified by MDAP (Formic).Fractions containing desired product were partitioned between sat.NaHCO₃ and DCM. The organic layer was separated, dried (Na₂SO₄) andconcentrated to give the product (11 mg, 0.027 mmol, 12%) as a whitesolid. The residue from the work up, which was insoluble in DCM wasdissolved in MeOH and concentrated to give 35 mg of crude orange oilysolid. This was purified directly by MDAP (Formic) to give a furtherbatch of product (13 mg, 0.032 mmol, 14%) as a slightly off-white solid.These two solids were combined to give final product (20 mg, 0.049 mmol,21(%) of an orange solid.

LCMS (2 mi Formic): Rt=0.80 min [MH]⁺=271.

The following were similarly prepared using BBr₃ to demethylate Examples363 & 365 respectively.

Rt (min) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ Method)425 (2S,3R,4R)-1-acetyl- 4-((4-chloro-3- hydroxyphenyl)amino)-2-cyclopropyl-3- methyl-1,2,3,4- tetrahydroquinoline-6-carboxamide

28 44 414 0.85 (2 min Formic) 426 (2S,3R,4R)-1-acetyl- 4-((4-chloro-2-hydroxyphenyl) amino)-2-cyclopropyl-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

11  8 414 0.91 (2 min Formic)

Example 427:(2S,3R,4R)-1-acetyl-4-((5-cyanothiophen-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

A mixture of(2S,3R,4R)-1-acetyl-4-((5-cyanothiophen-2-yl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 290, 21.1 mg, 0.053 mmol) andHATU (24.34 mg, 0.064 mmol) in anhydrous DMF (1 mL) was treated withDIPEA (0.037 mL, 0.213 mmol) and stirred in a sealed vial at rt for 15min. Ammonium chloride (8.56 mg, 0.160 mmol) was added and the mixturestirred for 1 h at rt. The mixture was directly purified by MDAP (HpH)to give the crude product 15 mg as a green solid. The sample was furtherpurified by MDAP (Formic) to title compound (5 mg, 24%) as a whitesolid. LCMS (2 min HpH): Rt=0.86 min, [MH]⁺=395.

Example 428:(2S,3R,4R)-1-acetyl-2-ethyl-4-((5-fluoro-4-methylpyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel(2S,3R,4R)-1-acetyl-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-ethyl-4-((5-fluoro-4-methylpyrimidin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 300, 37 mg, 0.068 mmol) in THE (3mL) was added. The solution was cooled to 0° C. and TBAF (1 M in THF)(0.272 mL, 0.272 mmol) was added and the reaction left to stir and warmto room temperature for 60 min. The reaction solution was poured ontowater (10 mL) and the aqueous phase extracted with DCM (3×10 mL). Theorganic extracts were combined, washed with brine (25 mL) and driedthrough a hydrophobic frit. The resulting solution was concentrated invacuo to give 54 mg of crude product as an orange/brown solid. This waspurified by chromatography on SiO₂ (10 g, eluting with 20-13%methanol/DCM). The fractions containing product were combined andconcentrated in vacuo to give 44 mg of crude product as an orange solid.This was purified by chromatography on SiO₂ (Biotage SNAP 10 g, elutingwith 0-7% methanol DCM). The fractions containing product were combinedand concentrated in vacuo to give the desired product as an orange solid(24 mg, 0.056 mmol, 82%). LCMS (2 min Formic): Rt=0.76 min, [MH]⁺=430.

The following examples were prepared in a similar manner to Example 428using TBAF to deprotect Intermediates 301-309.

Rt (mins) Ex. Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)429 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-4-((5- fluoro-4-methylpyrimidin-2- yl)amino)-N-(2- hydroxyethyl)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

11 55 442 0.79 (2 min Formic) 430 (2S,3R,4R)-1-acetyl- 4-((5-fluoro-4-methylpyrimidin-2- yl)amino)-N-(2- hydroxyethyl)-2,3- dimethyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

12 77 416 0.71 (2 min Formic) 431 (2S,3R,4R)-1-acetyl-2-ethyl-4-((5-fluoro- 6-methylpyridin-2- yl)amino)-N-(2-hydroxyethyl)-3- methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

66 64 429 0.63 (2 min Formic) 432 (2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5- fluoro-6- methylpyridin-2- yl)amino)-N-(2-hydroxyethyl)-3- methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

16 81 441 0.67 (2 min Formic) 433 (2S,3R,4R)-1-acetyl- 4-((5-fluoro-6-methylpyridin-2- yl)amino)-N-(2- hydroxyethyl)-2,3- dimethyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

21 74 415 0.58 (2 min Formic) 434 (2S,3R,4R)-1-acetyl- 2-ethyl-N-(2-hydroxyethyl)-3- methyl-4-((4- methylpyridin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

13 25 411 0.54 (2 min Formic) 435 (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2- hydroxyethyl)-3- methyl-4-((4- methylpyridin-2-yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

29 94 423 0.57 (2 min Formic) 436 (2S,3R,4R)-1-acetyl-N-(2-hydroxyethyl)- 2,3-dimethyl-4-((4- methylpyridin-2-yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

30 59 397 0.49 (2 min Formic) 437 (2S,3R,4R)-1-acetyl- 4-((4-cyano-2-fluorophenyl)amino)- 2-cyclopropyl-N-(2- hydroxyethyl)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

13.5 47 451 0.87 (2 min Formic)

Example 438:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(rac-2-methoxypropyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxypropyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 310, 42 mg, 0.096 mmol) intetrahydrofuran (THF) (3 mL) was added sodium hydride (4.23 mg, 0.106mmol). The reaction mixture was stirred at rt for 1 hr then a solutionof iodomethane (6.59 μL, 0.106 mmol) in tetrahydrofuran (THF) (1.000 mL)added dropwise. The reaction was stirred at rt for 3 hr. Further sodiumhydride (4.23 mg, 0.106 mmol) and iodomethane (6.59 μL, 0.106 mmol) wasadded. The reaction was stirred for 3 h. The reaction was quenched withwater, partitioned between ethyl acetate (50 mL) and saturated sodiumbicarbonate solution (10 mL) and extracted. The aqueous was extractedwith ethyl acetate (3×25 mL). The combined organics were washed withsaturated brine 10 mL, dried over magnesium sulphate and evaporated invacuo. The crude product was purified by MDAP (HpH) to afford a mixtureof mono- and di-methylated products. Further purification by MDAP(Formic) afforded the title compound (5 mg, 0.011 mmol, 12%) as a clearoil.

LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=451.

Example 439:(2S,3R,4R)-1-acetyl-N-ethyl-2,3-dimethyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

(2S,3R,4R)-1-Acetyl-4-amino-N-ethyl-2,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 313, 85 mg, 0.294 mmol) was treatedwith Pd₂(dba)₃ (40.3 mg, 0.044 mmol), sodium tert-butoxide (85 mg, 0.881mmol), DavePhos (11.56 mg, 0.029 mmol) and 2-bromo-6-methylpyridine (76mg, 0.441 mmol) and allowed to stir at 100° C. for 16 h. The reactionwas treated with further Pd₂(dba)₃ (26.9 mg, 0.029 mmol) and sodiumtert-butoxide (56.5 mg, 0.587 mmol) and allowed to stir at 100° C. for 4h. The reaction was allowed to cool to rt and was filtered throughcelite, washing with EtOAc. The eluent was concentrated and purified byMDAP (Formic). The appropriate fractions were summed and concentrated togive a yellow gum. This was eluted through a NH₂ SPE (5 g) with MeOH,the eluent was concentrated and dried to give the title compound (5 mg,0.013 mmol, 4%) as a yellow solid.

LCMS (2 min Formic): Rt=0.57 min, [MH]⁺=381.

The following examples were prepared in a similar manner to Example 439using Pd₂(dba)₃, DavePhos and NaOtBu to couple the appropriate arylhalide with Intermediate 313.

Rt (mins) Mass Yield (LCMS Ex. No. Name Structure (mg) (%) [MH]⁺ method)440 (2S,3R,4R)-1-acetyl- N-ethyl-2,3- dimethyl-4-((5- methylpyrazin-2-yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

49 41 382 0.69 (2 min Formic)

Example 441:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2-hydroxyethyl)-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

A solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 315, 35 mg, 0.092 mmol),2-aminoethanol (6.66 μl, 0.110 mmol), DIPEA (0.064 ml, 0.368 mmol) andHATU (42.0 mg, 0.110 mmol) in N,N-dimethylformamide (DMF) (1 mL) wasstirred in a closed vessel at room temp for 8 h. The reaction mixturewas purified directly by MDAP (Formic). The appropriate fractions werecombined and concentrated in vacuo to give the product (12 mg, 0.028mmol, 31%).

LCMS (2 min Formic): Rt=0.53 min, [MH]⁺=424.

Example 442:(2S,3R,4R)-1-acetyl-2-ethyl-N-(2-hydroxyethyl)-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a reaction vessel(2S,3R,4R)-1-acetyl-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-ethyl-3-methyl-4-((2-methylpyrimidin-4-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Intermediate 316, 35 mg, 0.067 mmol) intetrahydrofuran (THF) (3 mL) was added. The solution was cooled to 0° C.and TBAF (1 M in THF) (0.266 mL, 0.266 mmol) was added and the reactionleft to stir and warm to room temperature for 60 minutes. The reactionsolution was poured onto water (10 mL) and the aqueous phase extractedwith DCM (3×10 mL). The organic extracts were combined, washed withbrine (25 mL) and dried through a hydrophobic frit. The resultingsolution was concentrated in vacuo to give the crude product as a yellowsolid. This was purified by chromatography on SiO₂ (10 g, eluting with0-10% methanol/DCM). The fractions containing product were combined andconcentrated in vacuo to give 9 mg of desired product as a colourlessgum. The sample was dissolved in 1:1 MeOH:DMSO (1 mL) and purified byMDAP (HpH). The solvent was evaporated in vacuo to give 5 mg of titlecompound as a white solid.

LCMS (2 min Formic): Rt=0.50 min, [MH]⁺=412.

Example 443:(2S,3R,4R)-1-acetyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 318, 50 mg, 0.136 mmol) andHATU (61.9 mg, 0.163 mmol) in N,N-dimethylformamide (DMF) (0.8 mL) wasadded 4-aminotetrahydro-2H-thiopyran 1,1-dioxide (24.30 mg, 0.163 mmol)and DIPEA (0.095 mL, 0.543 mmol). The reaction mixture was stirred at rtfor 1 h. The reaction was diluted to 1 mL with methanol and purified byMDAP (HpH). The solvent was concentrated in vacuo to give the product(32 mg, 0.064 mmol, 47%) as an off-white solid. LCMS (2 min Formic):Rt=0.69 min, [MH]⁺=500.

The following examples were prepared in a similar manner to Example 443using HATU and DIPEA to couple the appropriate amine with Example 357(2-cPr) or Intermediate 318 (2-Et) or 320 (2-Me).

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)444 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3- methyl-4-((4-methylpyrimidin-2- yl)amino)-N-(oxetan- 3-yl)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

15 52 436 0.80 (2 min HpH) 445 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-N-(2-methoxyethyl)-3- methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

19 66 438 0.83 (2 min HpH) 446 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-N,3-dimethyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

20 77 394 0.80 (2 min HpH) 447 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-((4- methylpyrimidin-2- yl)amino)-N- (tetrahydro-2H-pyran-4-yl)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

22 72 464 0.84 (2 min HpH) 448 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-N-ethyl-3-methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

18 67 408 0.86 (2 min HpH) 449 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-N-(2-hydroxyethyl)-3- methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

38 68 424 0.74 (2 min HpH) 450 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-N-(1,1- dioxidotetrahydro- 2H-thiopyran-4-yl)- 3-methyl-4-((4-methylpyrimidin-2- yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

28 42 512 0.81 (2 min HpH) 451 (2S,3R,4R)-1-acetyl- 2-ethyl-N-(2-hydroxyethyl)-3- methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

60 71 412 0.61 (2 min Formic) 452 (2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4- ((4-methylpyrimidin- 2-yl)amino)-N- (tetrahydro-2H-pyran-4-yl)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

27 44 452 0.71 (2 min Formic) 453 (2S,3R,4R)-1-acetyl- 2-ethyl-N-(2-hydroxyethyl)-3- methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

23 41 412 0.61 (2 min Formic) 454 (2S,3R,4R)-1-acetyl- 2-ethyl-N-(2-methoxyethyl)-3- methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

21 36 426 0.80 (2 min HpH) 455 (2S,3R,4R)-1-acetyl- 2-ethyl-3-methyl-4-((4-methylpyrimidin- 2-yl)amino)-N- (oxetan-3-yl)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

45 78 424 0.77 (2 min HpH) 456 (2S,3R,4R)-1-acetyl- N,2-diethyl-3-methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

40 75 396 0.82 (2 min HpH) 457 (2S,3R,4R)-1-acetyl- N-(2-cyanoethyl)-2-ethyl-3-methyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

47 82 421 0.80 (2 min HpH) 458 (2S,3R,4R)-1-acetyl- N-(2-hydroxyethyl)-2,3-dimethyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

45 80 398 0.56 (2 min Formic) 459 (2S,3R,4R)-1-acetyl- N-(1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)- 2,3-dimethyl-4-((4-methylpyrimidin-2- yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

32 47 486 0.63 (2 min Formic) 460 (2S,3R,4R)-1-acetyl- N-(2-cyanoethyl)-2,3-dimethyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

43 75 407 0.74 (2 min HpH) 461 (2S,3R,4R)-1-acetyl- 2,3-dimethyl-4-((4-methylpyrimidin-2- yl)amino)-N- (tetrahydro-2H- pyran-4-yl)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

42 68 438 0.76 (2 min HpH) 462 (2S,3R,4R)-1-acetyl- N-ethyl-2,3-dimethyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

37 69 382 0.77 (2 min HpH) 463 (2S,3R,4R)-1-acetyl-N,2,3-trimethyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

38 73 368 0.71 (2 min HpH) 464 (2S,3R,4R)-1-acetyl- N-(3-methoxypropyl)-2,3- dimethyl-4-((4- methylpyrimidin-2-yl)amino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

48 80 426 0.79 (2 min HpH) 465 (2S,3R,4R)-1-acetyl- 2,3-dimethyl-4-((4-methylpyrimidin-2- yl)amino)-N-(oxetan- 3-yl)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

45 78 410 0.72 (2 min HpH) 466 (2S,3R,4R)-1-acetyl- N-isopropyl-2,3-dimethyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

41 74 396 0.84 (2 min HpH) 467 (2S,3R,4R)-1-acetyl- N-(2-methoxyethyl)-2,3-dimethyl-4-((4- methylpyrimidin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

40 69 412 0.75 (2 min HpH) 468 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-N-ethyl-3-methyl-4-((5- methylpyrazin-2- yl)amino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

20 30 408 0.77 (2 min Formic)

Example 469:(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((5-fluoropyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 327, 35 mg, 0.070 mmol) and HATU(32.1 mg, 0.084 mmol) in N,N-dimethylformamide (DMF) (0.6 mL) was addedtetrahydro-2H-pyran-4-amine (8.74 μL, 0.084 mmol) followed by DIPEA(0.049 mL, 0.281 mmol). The reaction mixture was stirred at rt for 1 h.The reaction mixture was purified by MDAP (HpH). The solvent wasevaporated in vacuo to afford the product (17 mg, 0.036 mmol, 52%) as awhite solid.

LCMS (2 min High pH): Rt=0.91 min, [MH]⁺=467.

The following examples were prepared in a similar manner to Example 404using HATU and DIPEA to couple the appropriate amine with Example 327(2-cPr) or 328 (2-Et) or Intermediate 321 (2-Me).

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)470 (2S,3R,4R)-1-acetyl-2- cyclopropyl-4-((5- fluoropyridin-2-yl)amino)-3-methyl-N- (oxetan-3-yl)-1,2,3,4- tetrahydroquinoline-6-carboxamide

22 96 439 0.87 (2 min HpH) 471 (2S,3R,4R)-1-acetyl-2- cyclopropyl-4-((5-fluoropyridin-2- yl)amino)-N-(2- methoxyethyl)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

15 83 441 0.91 (2 min HpH) 472 (2S,3R,4R)-1-acetyl-2- cyclopropyl-4-((5-fluoropyridin-2- yl)amino)-N-(2- hydroxyethyl)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

8 36 425 0.82 (2 min HpH) 473 (2S,3R,4R)-1-acetyl-2- cyclopropyl-N-(1,1-dioxidotetrahydro-2H- thiopyran-4-yl)-4-((5- fluoropyridin-2-yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline- 6-carboxamide

11 41 515 0.89 (2 min HpH) 474 (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-ethyl- 4-((5-fluoropyridin-2- yl)amino)-3-methyl- 1,2,3,4-tetrahydroquinoline- 6-carboxamide

17 79 411 0.94 (2 min HpH) 475 (2S,3R,4R)-1-acetyl-2- ethyl-4-((5-fluoropyridin-2- yl)amino)-N-(2- hydroxyethyl)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

25 27 415 0.55 (2 min TFA) 476 (2S,3R,4R)-1-acetyl- N,2-diethyl-4-((5-fluoropyridin-2- yl)amino)-3-methyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide

31 51 399 0.77 (2 min Formic) 477 (2S,3R,4R)-1-acetyl-2- ethyl-4-((5-fluoropyridin-2- yl)amino)-3-methyl-N- (tetrahydro-2H-pyran-4-yl)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

57 82 455 0.76 (2 min Formic) 478 (2S,3R,4R)-1-acetyl-2- ethyl-4-((5-fluoropyridin-2- yl)amino)-3-methyl-N- (oxetan-3-yl)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

33 51 427 0.70 (2 min Formic) 479 (2S,3R,4R)-1-acetyl-4-((5-fluoropyridin-2- yl)amino)-N-(2- hydroxyethyl)-2,3-dimethyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

18 29 401 0.53 (2 min TFA)

Example 480:(2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(3-methoxypropyl)-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 247, 25 mg, 0.066 mmol) and HATU(30.1 mg, 0.079 mmol) in N,N-dimethylformamide (DMF) (0.6 mL) was added3-methoxypropan-1-amine (8.32 μL, 0.079 mmol) and DIPEA (46 μL, 0.263mmol). The reaction mixture was stirred at rt for 1 h. The reactionmixture was purified directly by MDAP (HpH). The solvent was evaporatedin vacuo to afford the product (17 mg, 0.038 mmol, 57%) as a whitesolid.

LCMS (2 min High pH): Rt=0.97 min [MH]⁺=451.

The following example was prepared in a similar manner to Example 415using HATU and DIPEA to couple the appropriate amine with Example 247.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)481 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3- methyl-4-((6- methylpyridin-2-yl)amino)-N-(oxetan- 3-yl)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

26 91 435 0.57 (2 min Formic)

Example 482:(2S,3R,4R)-1-acetyl-2-cycloproyl-N-isopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Example 336, 91 mg, 0.248 mmol), HATU (113mg, 0.298 mmol), DIPEA (0.174 mL, 0.993 mmol) and N,N-dimethylformamide(DMF) (1.5 mL) were added. The reaction mixture was stirred at rt for 15min. To the reaction mixture propan-2-amine (0.064 mL, 0.745 mmol) wasadded. The reaction mixture was stirred at rt for 2 h 45 min. Thereaction mixture was partitioned between DCM and water. The organiclayer was dried and concentrated in vacuo, dissolved in DCM, loaded intoa 10 g SiO₂ cartridge and eluted with cyclohexane ethyl acetate(18-75%). The correct fractions were concentrated in vacuo to give anorange solid containing DMF. The solid was dissolved in ethyl acetateand washed with a 10% solution of LiCl in water (twice). The organiclayer was dried, concentrated in vacuo to give the title compound as acream solid.

LCMS (2 min Formic): Rt=0.80 min [MH]⁺=408.

The following examples were prepared in a similar manner to Example 417using HATU and DIPEA to couple the appropriate amine with Example 336(2-cPr) or Intermediate 323 (2-Me).

483 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-N- (1,3- dihydroxypropan-2-yl)-3-methyl-4- (pyrimidin-2- ylamino)-1,2,3,4- tetrahydroquinoline-6-carboxamide

29 24 440 0.61 (2 min Formic) 484 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-4-(pyrimidin- 2-ylamino)-N- (tetrahydro-2H- pyran-4-yl)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

76 56 450 0.73 (2 min Formic) 485 1-((2S,3R,4R)-2,3- dimethyl-4-(pyrimidin-2- ylamino)-6- (pyrrolidine-1- carbonyl)-3,4-dihydroquinolin- 1(2H)-yl)ethanone

11 19 394 0.69 (2 min Formic) 486 1-((2S,3R,4R)-2,3- dimethyl-6-(morpholine-4- carbonyl)-4- (pyrimidin-2- ylamino)-3,4- dihydroquinolin-1(2H)-yl)ethanone

19 32 410 0.62 (2 min Formic) 487 (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2- hydroxy-2- methylpropyl)-3- methyl-4-(pyrimidin-2-ylamino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

53 63 438 0.70 (2 min Formic) 488 (2S,3R,4R)-1-acetyl- 2-cyclopropyl-3-methyl-N-(oxetan-3- yl)-4-(pyrimidin-2- ylamino)-1,2,3,4-tetrahydroquinoline- 6-carboxamide

53 66 422 0.69 (2 min Formic) 489 (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2- methoxyethyl)-3- methyl-4-(pyrimidin-2-ylamino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

52 64 424 0.71 (2 min Formic) 490 (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(2- hydroxypropyl)-3- methyl-4-(pyrimidin-2-ylamino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

70 87 424 0.66 (2 min Formic) 491 (2S,3R,4R)-1-acetyl-2-cyclopropyl-N-(1- hydroxypropan-2- yl)-3-methyl-4- (pyrimidin-2-ylamino)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

49 61 424 0.67 (2 min Formic)

Example 492:(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-N-(2-hydroxyethyl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

(2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 325, 60 mg, 0.154 mmol) wasdissolved in N,N-dimethylformamide (DMF) (2 mL) and HATU (88 mg, 0.231mmol) was added followed by 2-aminoethanol (12 mg, 0.196 mmol) and DIPEA(0.09 mL, 0.515 mmol). Reaction mixture stirred under N2 at r.t. for 1.5days. Reaction mixture was concentrated to remove DMF and partitionedbetween ethyl acetate and sat. NaHCO₃ (aq.). The organic layer wasseparated, dried (Na₂SO₄) and conc. to give ˜153 mg of crude pink oil.This was purified by chromatography on SiO₂ (25 g cartridge, elutingwith 0-5% MeOH/DCM over 330 mL) to give the product (40 mg, 0.092 mmol,60%) as an off-white solid. LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=433.

The following examples were prepared in a similar manner to Example 492using HATU and DIPEA to couple the appropriate amine with Intermediate325.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)493 (2S,3R,4R)-1-acetyl- 4-((4- cyanophenyl)amino)- 2-cyclopropyl-N-(1,3- dihydroxypropan-2- yl)-3-methyl-1,2,3,4- tetrahydroquinoline-6-carboxamide

51 61 463 0.79 (2 min Formic) 494 (2S,3R,4R)-1-acetyl- 4-((4-cyanophenyl)amino)- 2-cyclopropyl-N-(2- (dimethylamino) ethyl)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

31 38 460 0.75 (2 min Formic) 495 (2S,3R,4R)-1-acetyl- 4-((4-cyanophenyl)amino)- 2-cyclopropyl-3- methyl-N-(2- (methylsulfonyl)ethyl)-1,2,3,4- tetrahydroquinoline- 6-carboxamide

65 73 495 0.87 (2 min Formic) 496 (2S,3R,4R)-1-acetyl- 4-((4-cyanophenyl)amino)- 2-cyclopropyl-N,3- dimethyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

29.5 68 403 0.89 (2 min Formic) 497 (2S,3R,4R)-1-acetyl- 4-((4-cyanophenyl)amino)- 2-cyclopropyl-N-(2- hydroxypropyl)-3-methyl-1,2,3,4- tetrahydroquinoline- 6-carboxamide

30.2 63 447 0.86 (2 min Formic) 498 (2S,3R,4R)-1-acetyl- 4-((4-cyanophenyl)amino)- 2-cyclopropyl-N-(2- methoxyethyl)-3- methyl-1,2,3,4-tetrahydroquinoline- 6-carboxamide

24 50 447 0.92 (2 min Formic)

Example 499:(2S,3R,4R)-1-acetyl-N-(2-aminoethyl)-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of tert-butyl(2-((2S,3R,4R)-1-acetyl-4-((4-cyanophenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxamido)ethyl)carbamate(for a preparation see Intermediate 326, 123 mg, 0.231 mmol) indichloromethane (DCM) (5 mL) was added TFA (1 mL, 12.98 mmol) andreaction mixture stirred at rt under N₂ for 2.5 h. The reaction mixturewas concentrated and loaded onto a 2 g SCX cartridge (pre-conditionedwith MeOH) and eluted with MeOH (30 mL) followed by 2M NH₃ in MeOH (30mL). Ammonia fractions containing product were combined and concentratedto give the product (71 mg, 0.165 mmol, 71%) as an off-white solid.

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=432.

The following examples (500-505) were prepared in a similar manner toExample 181, using DIPEA to couple the appropriate heteroaryl fluorideto Intermediate 332 (2-cPr) or 329 (2-Me).

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)500 1-((2S,3R,4R)-6-fluoro- 2,3-dimethyl-4-((4- methylpyrimidin-2-yl)amino)-3,4- dihydroquinolin-1(2H)- yl)ethanone

14 14 329 0.79 (2 min Formic) 501 1-((2S,3R,4R)-6-fluoro-2,3-dimethyl-4- (pyrimidin-2-ylamino)- 3,4-dihydroquinolin-1(2H)-yl)ethanone

9 10 315 0.78 (2 min Formic) 502 2-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3- methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)nicotinonitrile

137 66 365 1.05 (2 min Formic) 503 3-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3- methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)picolinonitrile

32 18 365 1.01 (2 min Formic) 504 2-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl- 1,2,3,4- tetrahydroquinolin-4-yl)amino)nicotinonitrile

54 36 339 0.96 (2 min Formic) 505 2-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3- methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)pyrimidine-4- carbonitrile

180 64 366 1.01 (2 min Formic)

The following examples (506-510) were prepared in a similar manner toExample 161, using Pd₂(dba)₃, DavePhos and NaOtBu to couple theappropriate aryl or heteroaryl halide to Intermediate 329.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)506 4-(((2S,3R,4R)-1-acetyl- 6-fluoro-2,3-dimethyl- 1,2,3,4-tetrahydroquinolin-4- yl)amino)-N- methylbenzamide

81 40 370 0.82 (2 min Formic) 507 6-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl- 1,2,3,4- tetrahydroquinolin-4-yl)amino)nicotinamide

1 3.3 357 0.61 (2 min Formic) 508 1-((2S,3R,4R)-6-fluoro-4-((3-methoxypyridin-2- yl)amino)-2,3-dimethyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

28 96 344 0.65 (2 min Formic) 509 1-((2S,3R,4R)-6-fluoro-4-((2-methoxypyridin-3- yl)amino)-2,3-dimethyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

22 76 344 1.05 (2 min Formic) 510 1-((2S,3R,4R)-6-fluoro-4-((4-methoxypyridin-2- yl)amino)-2,3-dimethyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

62 85 344 0.62 (2 min Formic)

Example 511:1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((3-methoxypyrazin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a 2-5 mL microwave vial,1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 332, 50 mg, 0.191 mmol) and sodiumtert-butoxide (73.3 mg, 0.762 mmol) were taken up in toluene (3 mL). Thesolutions were degassed with N₂ and the solutions were treated withPd₂(dba)₃ (17.45 mg, 0.019 mmol) and Q-Phos (13.58 mg, 0.019 mmol).2-chloro-3-methoxypyrazine (41.3 mg, 0.286 mmol) was added and thereaction was heated in a microwave reactor to 60° C. for 3 h. Thereaction mixture was filtered through celite and the celite washed withethyl acetate (2×15 mL). The combined filtrates were washed with 50:50sat. aqueous. Brine solution:water (2×30 mL) and the layers separated.The organic phase was dried through a hydrophobic frit and concentratedin vacuo to give 155 mg of the crude product as an orange/red solid.This was purified by chromatography on a 10 g silica gel column, elutingwith 0-40% ethyl acetate/cyclohexane. The appropriate fractions werecombined, concentrated in vacuo and dried under high vacuum to give thedesired product as an orange solid (67 mg, 0.181 mmol, 95%) LCMS (2 minFormic): Rt=1.05 min, [MH]⁺=371.

The following examples were prepared in a similar manner to Example 511using Pd₂(dba)₃, Q-Phos and NaOtBu to couple the appropriate aryl halideto Intermediate 332.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)512 1-((2S,3R,4R)-2- cyclopropyl-6- fluoro-4-((6- methoxypyridin-3-yl)amino)-3-methyl- 3,4-dihydroquinolin- 1(2H)-yl)ethanone

4 1.6 370 0.99 (2 min Formic) 513 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-3-methyl-4- ((6- (morpholinomethyl) pyridin-2-yl)amino)-3,4-dihydroquinolin- 1(2H)-yl)ethanone

26 48 439 0.74 (2 min Formic) 514 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-4-((2- methoxypyridin-4- yl)amino)-3-methyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

15 5.8 370 0.69 (2 min Formic) 515 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-4-((4- methoxypyridin-2- yl)amino)-3-methyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

8 3.1 370 0.70 (2 min Formic) 516 1-((2S,3R,4R)-2- cyclopropyl-4-((6-((dimethylamino) methyl)pyridin-2- yl)amino)-6-fluoro-3- methyl-3,4-dihydroquinolin- 1(2H)-yl)ethanone

104 63 397 0.75 (2 min Formic)

The following examples (517-521) were prepared in a similar manner toExample 165, using NaI and TMSCl to demethylate Intermediate 333, 334,335 or Example 509, 511.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)517 1-((2S,3R,4R)-6- fluoro-4-((2- hydroxypyrimidin-4- yl)amino)-2,3-dimethyl-3,4- dihydroquinolin- 1(2H)-yl)ethanone

5 52 331 0.56 (2 min Formic) 518 1-((2S,3R,4R)-6- fluoro-4-((2-hydroxypyridin-3- yl)amino)-2,3- dimethyl-3,4- dihydroquinolin-1(2H)-yl)ethanone

32 61 330 0.76 (2 min Formic) 519 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-4-((2- hydroxypyrimidin-4- yl)amino)-3-methyl-3,4-dihydroquinolin- 1(2H)-yl)ethanone

1.5 5.5 357 0.66 (2 min Formic) 520 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-4-((2- hydroxypyridin-3- yl)amino)-3-methyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

4.3 18 356 0.85 (2 min Formic) 521 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-4-((3- hydroxypyrazin-2- yl)amino)-3-methyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

50 91 357 0.75 (2 min Formic)

The following examples (522-529) were prepared in a similar manner toExample 320, using H₂O₂ to hydrolyse Examples 502-505, 538 orIntermediate 337-339.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)522 6-(((2S,3R,4R)-1-acetyl- 2-cyclopropyl-6-fluoro- 3-methyl-1,2,3,4-tetrahydroquinolin-4- yl)amino)nicotinamide

4.5 5 383 0.72 (2 min Formic) 523 2-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro- 3-methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)nicotinamide

101 78 383 0.82 (2 min Formic) 524 3-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro- 3-methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)picolinamide

12 41 383 1.00 (2 min Formic) 525 3-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro- 3-methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)pyrazine-2- carboxamide

15 24 384 0.95 (2 min Formic) 526 6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro- 3-methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)picolinamide

110 80 383 0.89 (2 min Formic) 527 2-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl- 1,2,3,4- tetrahydroquinolin-4-yl)amino)nicotinamide

33 60 357 0.83 (2 min HpH) 528 2-(((2S,3R,4R)-1-acetyl-6-fluoro-2,3-dimethyl- 1,2,3,4- tetrahydroquinolin-4- yl)amino)-6-methylnicotinamide

13 65 371 0.93 (2 min HpH) 529 2-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro- 3-methyl-1,2,3,4- tetrahydroquinolin-4-yl)amino)pyrimidine-4- carboxamide

65 52 384 0.83 (2 min Formic)

Example 530:1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((3-hydroxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((3-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 336, 50 mg, 0.135 mmol) and lithiumiodide (362 mg, 2.71 mmol) in NMP (2 mL) was stirred under microwaveradiation in a closed vessel at 200° C. for 30 min. 1 mL of theremaining solution was then purified by MDAP (High pH). The appropriatefractions were combined and concentrated in vacuo to give the desiredproduct (4.4 mg, 0.012 mmol, 9%). LCMS (2 min Formic): Rt=0.67 min,[MH]⁺=356.

The following examples were prepared in a similar manner to Example 530,using Lil to demethylate Examples 512, 514 or 515.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)531 1-((2S,3R,4R)-2- cyclopropyl-6- fluoro-4-((2- hydroxypyridin-4-yl)amino)-3-methyl- 3,4-dihydroquinolin- 1(2H)-yl)ethanone

11 15 356 0.73 (2 min Formic) 532 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-4-((4- hydroxypyridin-2- yl)amino)-3-methyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

15 21 356 0.65 (2 min Formic) 533 1-((2S,3R,4R)-2- cyclopropyl-6-fluoro-4-((6- hydroxypyridin-3- yl)amino)-3-methyl- 3,4-dihydroquinolin-1(2H)-yl)ethanone

4 8.7 356 0.77 (2 min Formic)

The following examples (534-537) were prepared in a similar manner toExample 249, using HATU and DIPEA to couple the appropriate amine withIntermediate 341.

Rt (mins) Ex Mass Yield (LCMS No. Name Structure (mg) (%) [MH]⁺ method)534 4-(((2S,3R,4R)-1- acetyl-2- cyclopropyl-6- fluoro-3-methyl- 1,2,3,4-tetrahydroquinolin- 4- yl)amino)benzamide

23 48 382 0.88 (2 min Formic) 535 4-(((2S,3R,4R)-1- acetyl-2-cyclopropyl-6- fluoro-3-methyl- 1,2,3,4- tetrahydroquinolin-4-yl)amino)-N- methylbenzamide

24 49 396 0.92 (2 min Formic) 536 4-(((2S,3R,4R)-1- acetyl-2-cyclopropyl-6- fluoro-3-methyl- 1,2,3,4- tetrahydroquinolin-4-yl)amino)-N,N- dimethylbenzamide

31 62 410 1.00 (2 min Formic) 537 4-(((2S,3R,4R)-1- acetyl-2-cyclopropyl-6- fluoro-3-methyl- 1,2,3,4- tetrahydroquinolin-4-yl)amino)-N- isopropylbenzamide

32 61 424 1.03 (2 min Formic)

Example 538:3-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile

A solution of1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 332, 100 mg, 0.381mmol), 3-chloropyrazine-2-carbonitrile (106 mg, 0.762 mmol) andtriethylamine (0.106 mL, 0.762 mmol) in N-methyl-2-pyrrolidone (2 mL)was stirred in a closed vessel in the microwave at 200° C. for 1.5 h.The solution was diluted with ethyl acetate (4 mL) and washed with water(3×4 mL). The organic layer was concentrated in vacuo to give 270 mgcrude material. The material was dissolved in 1:1 MeOH:DMSO (3×1 mL) andpurified by MDAP (Formic). The fractions from the first run werecombined and concentrated in vacuo to give the desired product (22 mg,0.060 mmol, 16%).

LCMS (2 min Formic): Rt=1.02 min, [MH]⁺=366.

Example 539:1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((6-(piperazin-1-ylmethyl)pyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

In a 50 mL flask, 4M HCl in 1,4-dioxane (1.07 mL, 4.28 mmol) was addedto a stirred solution of tert-butyl4-((6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-fluoro-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2-yl)methyl)piperazine-1-carboxylate(for a preparation see Intermediate 342, 76.7 mg, 0.143 mmol) in1,4-dioxane (3 mL). The resulting solution was left stirring for 1 h atrt. Volatiles were removed under reduced pressure to afford 95.8 mg ofyellow gum. This resulting crude gum was dissolved in MeOH and loaded ona 5 g SCX cartridge, washed with methanol (3 CV) and flushed withMeOH/NH₃ (2M) (3 CV). The appropriate ammonia fractions were combinedand volatiles removed under reduced pressure to afford 61.9 mg of yellowgum. This gum was purified by MDAP (Formic) to give the desired product(40.7 mg, 0.093 mmol, 65%).

LCMS (2 min Formic): Rt=0.56 min, [MH]⁺=438.

Example 540:rac-4-(((2S,3R,4R)-1-acetyl-6-(4-acetylpiperazin-1-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile

To a dried flask under nitrogen was added a solution ofrac-4-(((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzonitrile(for a preparation see Example 219, 10.1 mg, 0.019 mmol) indichloromethane (DCM) (1 mL), followed by N,N-diisopropylethylamine(0.034 mL, 0.194 mmol) and acetyl chloride (6.88 μL, 0.097 mmol). Themixture was allowed to stir at rt for 45 min. The reaction mixture wasdiluted with dichloromethane and washed with 2M HCl solution (2×20 mL)and saturated sodium hydrogen carbonate solution (20 mL). The organiclayer was passed over a hydrophobic frit and concentrated in vacuo toafford a transparent yellow solid product (7.8 mg, 0.016 mmol, 83%).

LCMS (2 min Formic): Rt=0.89 min, [MH]⁺=460.

The following examples (541-544) were prepared in a similar manner toIntermediate 358 using KF, 18-crown-6 and DIPEA to couple theappropriate aryl halide to Intermediate 81 or 357; followed bydeprotection with TFA as described for Example 87.

Rt (mins) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ method)541 rac-5-(((2S,3R,4R)-1- acetyl-2,3-dimethyl-6- (1,2,3,6-tetrahydropyridin-4-yl)- 1,2,3,4- tetrahydroquinolin-4-yl)amino)pyrazine-2- carbonitrile

10 53 403 0.63 (2 min Formic) 542 rac-6-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6- (1,2,3,6- tetrahydropyridin-4-yl)- 1,2,3,4-tetrahydroquinolin-4- yl)amino)nicotinonitrile

7 48 402 0.64 (2 min Formic) 543 rac-6-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3- methyl-6-(1,2,3,6- tetrahydropyridin-4-yl)-1,2,3,4- tetrahydroquinolin-4- yl)amino)nicotinonitrile

54 42 428 0.71 (2 min Formic) 544 rac-5-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-3- methyl-6-(1,2,3,6- tetrahydropyridin-4-yl)-1,2,3,4- tetrahydroquinolin-4- yl)amino)pyrazine-2- carbonitrile

69 53 429 0.68 (2 min Formic)

The following examples (545-550) were prepared in a similar manner toExample 81 using Pd₂(dba)₃, DavePhos and NaOtBu to couple theappropriate aryl halide with Intermediate 81 or 357; followed bydeprotection with TEA as described for Example 87.

Rt (mins) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ method)545 rac-4-(((2S,3R,4R)-1- acetyl-2,3-dimethyl-6- (1,2,3,6-tetrahydropyridin-4-yl)- 1,2,3,4- tetrahydroquinolin-4-yl)amino)benzonitrile

5 44 401 0.72 (2 min Formic) 546 rac-1-((2S,3R,4R)-2,3- dimethyl-4-((6-methylpyridin-2- yl)amino)-6-(1,2,3,6- tetrahydropyridin-4-yl)-3,4-dihydroquinolin- 1(2H)-yl)ethanone

14 90 391 0.90 (2 min HpH) 547 rac-1-((2S,3R,4R)-2,3- dimethyl-4-((4-methylpyrimidin-2- yl)amino)-6-(1,2,3,6- tetrahydropyridin-4-yl)-3,4-dihydroquinolin- 1(2H)-yl)ethanone

5 52 392 0.79 (2 min HpH) 548 rac-1-((2S,3R,4R)-2,3- dimethyl-4-((5-methylpyrazin-2- yl)amino)-6-(1,2,3,6- tetrahydropyridin-4-yl)-3,4-dihydroquinolin- 1(2H)- yl)ethanonecarboxamide

6 48 392 0.77 (2 min HpH) 549 rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4- ((5-methylpyrazin-2- yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)- 3,4-dihydroquinolin- 1(2H)-yl)ethanone

50 40 418 0.66 (2 min Formic) 550 rac-1-((2S,3R,4R)-2-cyclopropyl-4-((5- fluoropyridin-2- yl)amino)-3-methyl-6- (1,2,3,6-tetrahydropyridin-4-yl)- 3,4-dihydroquinolin- 1(2H)-yl)ethanone

59 46 421 0.68 (2 min Formic)

Examples 551a & 551b:4-(((2R,3S,4S)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide(551a) &4-(((2S,3R,4R)-1-acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide(551b)

rac-4-(((2S,3R,4R)-1-Acetyl-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-methylbenzamide(for a preparation see Example 178, 90, ˜40 mg) was submitted for chiralseparation into its enantiomers (A and B) using a 250×20 mm Chiralpak ICcolumn eluting with 50% ethanol in 50% heptane at a flow rate of 17.5mL/min. Peak 1/Enantiomer A fractions were collected between 9 and 13min. Peak 2/Enantiomer B fractions were collected between 16 and 20 min.Fraction solutions were combined then evaporated to dryness to giveEnantiomer A (19.5 mg) and Enantiomer B (22.4 mg) as white solids.

Enantiomer A, Example 551a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 50% ethanol in heptanes at 1 mL/min—Rt=8.9 min. >99% ee by UV.

Enantiomer B, Example 551 b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 10% ethanol in heptane (plus 0.2% isopropylamine) at 1mL/min—Rt=13.0 min, >99% ee by UV.

Example 552:rac-6-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile

To a microwave vial 6-fluoronicotinonitrile (30.3 mg, 0.248 mmol),rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 152, 37.5 mg, 0.124 mmol), and DIPEA(0.065 mL, 0.372 mmol) were added and the reaction heated to 200° C. ina microwave reactor for 30 minutes. The reaction mixture was diluted to2 ml with methanol and purified in 2 batches by MDAP (Formic). The cleanfractions from both runs were combined and the solvent was evaporated invacuo to give 21 mg of product as a yellow solid. This was dissolved inmethanol and run through a pre-equilibrated —NH₂ column (5 g) in orderto form the free base. The methanol was evaporated in vacuo to give 17mg of product.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=405.

Example 553:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((5-methylpyrazin-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Therac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 179, 46 mg, 0.110 mmol) was taken up inethanol (5 mL) and the reaction was hydrogenated using the H-cube(settings: 25° C., 1 bar, 1 ml/min flow rate) and 10% Pd/C CatCart 30 asthe catalyst. The reaction was concentrated and dried to give theproduct. This was further purified using a MDAP (Formic). Theappropriate fraction was concentrated to give the product (5 mg, 0.012mmol, 11%) as a white solid. LCMS (2 min Formic): Rt=0.92 min,[MH]⁺=421.

Example 554:1-((rac-2S,3R,4R)-2-cyclopropyl-3-methyl-6-((S)-3-methylpiperazin-1-yl)-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a stirring solution of (S)-tert-butyl4-((rac-2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate(for a preparation see Intermediate 343, 18 mg, 0.034 mmol) indichloromethane (DCM) (1 mL) under nitrogen was added trifluoroaceticacid (0.25 mL, 3.24 mmol). The mixture was stirred at rt for 1 h. Thereaction mixture was concentrated in vacuo. The residue was dissolved inmethanol and loaded onto a 1 g SCX SPE cartridge, which had beenpre-equilibrated with methanol. The column was first eluted withmethanol into one fraction, and then the product was eluted into aseparate fraction with 2M NH₃ in methanol. The appropriate fraction wasconcentrated in vacuo to afford the product. The sample was dissolved in1:1 MeOH:DMSO 1 mL and purified by MDAP (HpH). The solvent wasevaporated in vacuo to give the required product (1.5 mg).

LCMS (2 min HpH): Rt=0.83 min, [MH]⁺=435.

Example 555:1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 0.5-2 mL microwave vial was evacuated and back filled with nitrogen.1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 345, 95 mg, 0.291 mmol) inN-methyl-2-pyrrolidone (NMP) (1.6 mL) was then added. To this was added2-fluoropyrimidine (57.1 mg, 0.582 mmol), and DIPEA (0.152 mL, 0.873mmol) and the resultant solution then heated in a microwave reactor to150° C. for 30 min, then 45 min, then 30 min and finally 30 min at 170°C. The reaction mixture was filtered through a cotton wool plug directlyinto two LCMS vials and was then purified by 2×MDAP (Formic). Not all ofthe crude sample was injected by the machine so two further MDAPs(Formic) were run. All of the appropriate fractions were collected andconcentrated in vacuo to afford the desired product as an off-whitecrystalline solid (57 mg, 0.141 mmol, 48%).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=405.

Example 556:1-((2S,3R,4R)-2-cyclopropyl-6-(2-hydroxyethoxy)-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel1-((2S,3R,4R)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 348, 43 mg, 0.084 mmol) intetrahydrofuran (THF) (9 mL) was added. The solution was cooled to 0° C.and TBAF (1 M in THF) (0.337 mL, 0.337 mmol) was added and the reactionleft to stir and warm to rt for 60 minutes. The reaction solution waspoured onto water (10 mL) and the aqueous phase extracted with DCM (3×10mL). The organic extracts were combined, washed with brine (25 mL) anddried through a hydrophobic frit. The resulting solution wasconcentrated in vacuo to give 53 mg of crude product as an orange gum.The sample was dissolved in 1:1 DMSO:methanol (1.5 mL) and purified byMDAP (Formic). The solvent was evaporated in vacuo to give the product(12 mg, 0.030 mmol, 36%) as an off-white solid. LCMS (2 min Formic):Rt=0.74 min, [MH]⁺=397.

Example 557:1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((4-methylpyrimidin-2-4)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The 2-chloro-4-methylpyrimidine (200 mg, 1.556 mmol), 18-crown-6 (586mg, 1.556 mmol) and potassium fluoride (108 mg, 1.867 mmol) weresuspended in N-methyl-2-pyrrolidone (NMP) (5 mL) and irradiated in amicrowave at 200° C. for 1 h. The reaction was treated with1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 350, 85 mg, 0.231mmol) and DIPEA (0.136 mL, 0.778 mmol) and was irradiated in a microwaveat 180° C. for 30 mins. The reaction was partitioned between 10%LiCl(aq) and EtOAc, the organic layer was dried using a hydrophobic fritand concentrated to a gum, this gum was purified using MDAP (Formic).The appropriate fraction was concentrated and eluted through a NH₂ SPE(1 g) with MeOH, the eluent was concentrated and dried to give theproduct (5 mg, 10.86 μmol, 1%). LCMS (2 min Formic): Rt=0.83 min[MH]⁺=461.

The following examples were prepared in a similar manner to Example 557using Pd₂(dba)₃, DavePhos and NaOtBu to couple the appropriate arylhalide with Intermediate 352.

Rt (mins) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ method)558 4-(((2S,3R,4R)-1-acetyl- 2-cyclopropyl-6-(1-(2- hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl- 1,2,3,4- tetrahydroquinolin-4-yl)amino)pyridin-2(1H)- one

4 6 448 0.65 (2 min HpH) 559 1-((2S,3R,4R)-2- cyclopropyl-6-(1-(2-hydroxyethyl)-1H- pyrazol-4-yl)-3-methyl- 4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin- 1(2H)-yl)ethanone

55 64 433 0.72 (2 min Formic) 560 1-((2S,3R,4R)-2- cyclopropyl-4-((5-fluoropyridin-2- yl)amino)-6-(1-(2- hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl- 3,4-dihydroquinolin- 1(2H)-yl)ethanone

5 8 450 0.77 (2 min Formic) 561 1-((2S,3R,4R)-2- cyclopropyl-4-((5-fluoro-6-methylpyridin- 2-yl)amino)-6-(1-(2- hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl- 3,4-dihydroquinolin- 1(2H)-yl)ethanone

6 8 464 0.78 (2 min Formic) 562 1-((2S,3R,4R)-2- cyclopropyl-6-(1-(2-hydroxyethyl)-1H- pyrazol-4-yl)-3-methyl- 4-((4-methylpyrimidin-2-yl)amino)-3,4- dihydroquinolin-1(2H)- yl)ethanone

25 45 447 0.73 (2 min Formic) 563 1-((2S,3R,4R)-2- cyclopropyl-6-(1-(2-hydroxyethyl)-1H- pyrazol-4-yl)-3-methyl- 4-((6-methylpyridin-2-yl)amino)-3,4- dihydroquinolin-1(2H)- yl)ethanone

8 8 446 0.65 (2 min Formic)

Example 564:1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel1-((2S,3R,4R)-6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 355, 70 mg, 0.128 mmol) intetrahydrofuran (THF) (3 mL) was added. The solution was cooled to 0° C.and TBAF (1 M in THF) (0.513 mL, 0.513 mmol) was added and the reactionleft to stir and warm to rt under N₂ for 1 h. The reaction mixture wasdiluted with water (10 mL) and DCM (10 ml). The organic layer wasseparated and aqueous layer was further extracted with DCM (3×10 mL).The combined organic extracts were dried (Na₂SO₄) and concentrated togive ˜79 mg crude pink residue. This was purified by chromatography onSiO₂ (25 g cartridge, eluting with 0-10% methanol/DCM over 330 mL,followed by 10-20% methanol/DCM over 170 mL) to give the product (46 mg,0.107 mmol, 83%) as a colourless oil. LCMS (2 min Formic): Rt=0.61 min,[MH]⁺=432.

Example 565:1-((2S,3R,4R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A sample of1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 359, 22.3 mg, 0.046 mmol) wasdissolved in dichloromethane (DCM) (1 mL) and placed in a dried flaskunder nitrogen. To this was added N,N-diisopropylethylamine (0.080 mL,0.456 mmol), followed by acetyl chloride (0.016 mL, 0.228 mmol). Themixture was allowed to stir for 90 min. The reaction mixture was dilutedwith dichloromethane, and washed with 2M aqueous HCl (2×20 mL) followedby saturated aqueous sodium hydrogen carbonate solution (2×20 mL). Theorganic layer was then passed through a hydrophobic frit, collected andconcentrated in vacuo. The crude residue was dissolved in 1:1 MeOH:DMSO(1 mL) and purified by MDAP (Formic). The solvent was evaporated invacuo to give the required product (4.8 mg, 9.96 μmol, 22%).

LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=434.

Example 566:1-((2S,3R,4R)-6-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A dried flask under nitrogen was charged with a sample of1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 359, 34.2 mg, 0.087 mmol), which wasthen dissolved in dichloromethane (DCM) (1 mL). To this stirringsolution was added 2-bromoethanol (0.015 mL, 0.218 mmol), and themixture was left to stir at rt for 16 h. The reaction mixture wasconcentrated in vacuo, taken up in dichloromethane and loaded onto a 10g silica flash column, and eluted by flash silica gel chromatography,eluting in 6%-10% 2M NH₃/MeOH in dichloromethane. The purest fractionswere combined and concentrated in vacuo to afford a pale yellow glass(11.1 mg, 0.024 mmol, 28%). LCMS (2 min Formic): Rt=0.57 min, [MH]⁺=436.

Example 567:1-((2S,3R,4R)-2,3-dimethyl-4-((4-methylpyrimidin-2-yl)amino)-rac-6-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a 10 mL-20 mL microwave vial was added 2-chloro-4-methylpyrimidine(127 mg, 0.986 mmol), potassium fluoride (86 mg, 1.478 mmol) and18-crown-6 (130 mg, 0.493 mmol), followed by a solution of1-((2S,3R,4R)-4-amino-2,3-dimethyl-rac-6-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 363, 100 mg, 0.329 mmol) and DIPEA(0.287 mL, 1.643 mmol) in dimethyl sulfoxide (DMSO) (5 mL). The reactionvessel was sealed and heated to 160° C. for 4 h. The reaction mixturewas partitioned between diethyl ether (25 mL) and water (25 mL). Thelayers were separated and the aqueous layer was extracted with diethylether (2×25 mL). The organic layer was dried through a hydrophobic fritand concentrated in vacuo to give 189 mg of crude product as an orangeoil. This was purified by chromatography on SiO₂ (10 g) eluting with50-100% ethyl acetate/cyclohexane. The fractions containing product werecombined and concentrated in vacuo to give 46 mg of desired product (46mg, 0.116 mmol, 35%) as a yellow solid.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=397.

Example 568:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-rac-6-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a reaction vessel1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-rac-6-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 366, 184 mg, 0.557 mmol),2-bromo-4-methylpyrimidine (193 mg, 1.114 mmol) and sodium tert-butoxide(268 mg, 2.78 mmol) were added in 1,4-dioxane (10 mL). This solution wastreated with Pd₂(dba)₃ (76 mg, 0.084 mmol) and DavePhos (43.8 mg, 0.111mmol) and left to stir at 100° C. for 3 h. Further2-bromo-4-methylpyrimidine (150 mg, 0.867 mmol), DavePhose (43 mg, 0.109mmol), and Pd₂(dba)₃ (78 mg, 0.085 mmol) were added and the reactionleft to stir for 1 h. Pd₂(dba)₃ (670 mg, 0.732 mmol) and DavePhos (40mg, 0.102 mmol) were added and the reaction left to stir at 100° C. for19 h. The reaction mixture was filtered through celite and the celitewashed with ethyl acetate (15 mL). The combined filtrates were washedwith sat. aq. NaHCO₃ (2×25 mL) and the layers separated. The organicphase was dried through a hydrophobic frit and concentrated in vacuo togive 592 mg of crude product as a brown gum. This was purified bychromatography on SiO₂ (25 g, eluting with 0-100% ethylacetate/cyclohexane). The fractions containing product were combined andconcentrated in vacuo to give 90 mg of product as a brown gum. Thesample was dissolved in 1:1 MeOH:DMSO (1 mL) and (47 mg, 0.111 mmol,20%) as an off-white solid.

LCMS (2 min HpH): Rt=0.95 min, [MH]⁺=423.

Example 569:1-((2S,3R,4R)-2,3-dimethyl-6-(piperazin-1-yl)-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone,hydrochloride

To a flask containing tert-butyl4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 367, 119 mg, 0.248 mmol) indichloromethane (DCM) (1 mL) was added TFA (300 μL, 3.89 mmol) and thereaction was stirred for 1 h. The reaction mixture was concentrated invacuo to afford a brown oil. This was dissolved in methanol and loadedonto an SCX cartridge (5 g). It was eluted with methanol (3 CVs) andproduct eluted as free base with 2M ammonia in methanol. The filtratefrom the ammonia fractions was concentrated in vacuo to yield a yellowoil. This was taken up in DMSO/MeOH (1:1, 1.8 mL) and purified by MDAP(HpH) The fractions were combined together and concentrated in vacuo toafford the desired product as a pale yellow glass (75 mg, 0.197 mmol,80%). 45 mg of the sample was used in subsequent chemistry the other 30mg was taken up in dichloromethane (DCM) (1.0 mL) in a vial. HCl (1M inEt₂O) (79 μL, 0.079 mmol) was added and the sample sonicated for 2 minand allowed to stand for 15 min before the solvents were removed under astream of nitrogen and the sample further dried in vacuo to afford thedesired HCl salt (35.2 mg, 0.084 mmol, 34%). LCMS (2 min Formic):Rt=0.53 min, [MH]⁺=381.

Example 570:1-((2S,3R,4R)-6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,3-dimethyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A dried flask under nitrogen was charged with a sample of1-((2S,3R,4R)-2,3-dimethyl-6-(piperazin-1-yl)-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 569, 20 mg, 0.053 mmol), which was thendissolved in dichloromethane (DCM) (2 mL). To this stirring solution wasadded 2-bromoethanol (0.019 mL, 0.263 mmol), and the mixture was left tostir at rt for 72 h. Further 2-bromoethanol (0.019 mL, 0.263 mmol) wasadded and the reaction stirred for a further 5 h. Triethylamine (0.073mL, 0.526 mmol) was added (solution turned yellow) and the reactionstirred for 24 h. The reaction mixture was loaded directly onto a 10 gsilica flash column, and eluted by flash silica gel chromatography,eluting in 0%-50% (20% (2M NH₃/MeOH) in dichloromethane) in DCM. Theappropriate fractions were collected and combined to afford the productas a white solid (42 mg). This was taken up in 1:1 MeOH/DMSO (0.9 mL)and purified by MDAP (HpH). The appropriate fraction was collected andconcentrated in vacuo to afford the desired product as a colourless oil(14.7 mg, 0.035 mmol, 66%).

LCMS (2 min Formic): Rt=0.52 min, [MH]⁺=425.

Example 571:4-(((2S,3R,4R)-1-acetyl-2,3-dimethyl-6-(piperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzamide

tert-Butyl4-((2S,3R,4R)-1-acetyl-4-((4-carbamoylphenyl)amino)-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 370, 52 mg, 0.100 mmol) was taken upin DCM (5 mL). Trifluoroacetic acid (0.1 mL, 1.298 mmol) was added, andthe reaction left to stir for 1 h at rt. Further trifluoroacetic acid(0.1 ml, 1.298 mmol) was added and the reaction was left to stir for 16h at rt. The reaction solution was concentrated in vacuo then retaken upin DCM (5 mL) and concentrated in vacuo to give the crude product as acolourless oil. This was retaken up in methanol and purified bysulphonic acid SPE (SCX) 5 g using a sequential solvents methanol, 2Mammonia/methanol. The appropriate fractions were combined andconcentrated in vacuo to give 35 mg of the desired product as anoff-white solid.

LCMS (2 min Formic): Rt=0.54 min, [MH]⁺=422.

Example 572:4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-1-methylpiperazin-2-one

A solution of1-((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 371, 165 mg, 0.411 mmol),1-methylpiperazin-2-one, hydrochloride (124 mg, 0.822 mmol), DavePhos(16.18 mg, 0.041 mmol), Pd₂(dba)₃ (18.83 mg, 0.021 mmol) and sodiumtert-butoxide (158 mg, 1.645 mmol) in 1,4-dioxane (5 mL) was stirredunder nitrogen at 90° C. for 16 h. The reaction mixture was allowed tocool to rt, filtered through celite and rinsed with ethyl acetate. Thesolvent was evaporated in vacuo and the remaining mixture was dissolvedin 1,4-dioxane (5 mL). 1-methylpiperazin-2-one, hydrochloride (124 mg,0.822 mmol), DavePhos (16.18 mg, 0.041 mmol), Pd₂(dba)₃ (18.83 mg, 0.021mmol) and sodium tert-butoxide (158 mg, 1.645 mmol) were added and thereaction was heated under nitrogen at 90° C. for a further 16 h. Thereaction mixture was allowed to cool to rt, filtered through celite andrinsed with ethyl acetate. The solvent was evaporated in vacuo and thecrude was re-dissolved in DCM. This solution was applied to a 50 gsilica cartridge and purified over a gradient of 0-50% ethyl acetate incyclohexane over 12 CVs. The appropriate fractions were combined andconcentrated in vacuo to give the product (34 mg, 0.078 mmol, 19%).

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=435.

Example 573:1-((2S,3R,4R)-2-ethyl-3-methyl-6-(piperazin-1-yl)-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 376, 51 mg, 0.103 mmol) indichloromethane (DCM) (4 mL) was added TFA (1 ml, 12.98 mmol) andreaction mixture was stirred under nitrogen at rt. Reaction mixture wasconcentrated and loaded onto a 2 g SCX cartridge (pre-conditioned withMeOH) and eluted with MeOH (30 mL) followed by 2M NH₃ in MeOH (30 mL).Ammonia fractions were combined and concentrated to give the product (39mg, 0.099 mmol, 96%) as a pale yellow solid. LCMS (2 min Formic):Rt=0.56 min, [MH]⁺=395.

Example 574:1-((2S,3R,4R)-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of tert-butyl4-((2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 377, 346 mg, 0.704 mmol) indichloromethane (DCM) (4 mL) was added TFA (1 mL, 12.98 mmol) andreaction mixture stirred at rt under nitrogen. Reaction mixture turneddark orange colour on addition of TFA. The reaction mixture wasconcentrated and loaded onto a 2 g SCX cartridge (pre-conditioned withMeOH) and eluted with MeOH (30 ml) followed by 2M NH₃ in MeOH (30 mL).Ammonia fractions containing product were combined and concentrated togive the product (219 mg, 0.559 mmol, 79%) as a pale yellow foamy solid.

LCMS (2 min Formic): Rt=0.59 min, [MH]⁺=392.

Example 575:1-((2S,3R,4R)-2-ethyl-6-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of1-((2S,3R,4R)-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 574, 66 mg, 0.169 mmol) indichloromethane (DCM) (2 mL) was added 2-bromoethanol (0.036 mL, 0.506mmol) dropwise. The reaction mixture was stirred at rt for 1.5 h. Thereaction mixture was concentrated to give ˜150 mg of crude yellowresidue. This was purified by chromatography on SiO₂ (10 g) eluting with0-20% methanol/DCM over 120 mL to the product (31 mg, 0.071 mmol, 42%yield) as a pale yellow solid. LCMS (2 min Formic): Rt=0.59 min,[MH]⁺=436.

Example 576:1-((2S,3R,4R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a solution of1-((2S,3R,4R)-2-ethyl-3-methyl-4-(pyrimidin-2-ylamino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 574, 30 mg, 0.077 mmol) indichloromethane (DCM) (2 mL) was added DIPEA (0.027 mL, 0.153 mmol)followed by acetyl chloride (6.54 μL, 0.092 mmol) in dichloromethane(DCM) (1 mL). The reaction mixture was stirred under nitrogen at rt. Thereaction mixture was diluted with DCM and H₂O. 2M aq. HCl was added andthe organic layer was separated. The organic layer was then washed withsat. NaHCO₃ solution dried (Na₂SO₄) and concentrated to give 45 mg ofcrude residue. This was purified by MDAP (Formic). Fractions containingproduct were partitioned between sat. NaHCO₃ solution (10 mL) and DCM(30 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated to give the product (18 mg, 0.042 mmol, 54%) as a whitesolid.

LCMS (2 min Formic): Rt=0.78 min, [MH]⁺=434.

Example 577:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A flask under Nitrogen was charged with a sample of tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(for a preparation see Intermediate 378, 295.2 mg, 0.586 mmol). Thematerial was dissolved in dichloromethane (DCM) (12 mL), and to thissolution was added trifluoroacetic acid (3 mL, 38.9 mmol). The mixturewas left to stir at rt for ˜ 20 min. The reaction mixture wasconcentrated in vacuo. The residue was taken up in methanol and loadedonto a 10 g SCX-2 SPE cartridge, which had been pre-wet with methanol.The column was washed with 2CVs of methanol, and the product was theneluted in 2CVs of 2M methanolic ammonia. The fractions were analysed byTLC, and the appropriate fractions were collected and concentrated invacuo to afford a transparent yellow glass (179.4 mg, 0.422 mmol, 72%).

LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=404.

Example 578:1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

To a flask under nitrogen was added a sample of1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 577, 50 mg, 0.124 mmol), which had beendissolved in dichloromethane (DCM) (1 mL). The solution was stirred, andto it was added 2-bromoethanol (0.018 mL, 0.248 mmol). The mixture wasleft to stir at rt for 1 h. The reaction mixture was concentrated invacuo. The residue was taken up in dichloromethane, loaded onto a 10 gsilica column, and the mixture was purified by flash silica gelchromatography—the product eluting in 7.5%-12.5% 2M methanolicammonia/dichloromethane. The appropriate fractions were collected andconcentrated in vacuo to afford a colourless glass. Some startingmaterial remained so the sample was dissolved in dichloromethane (DCM)(1 mL), and then to this solution was added DIPEA (0.043 mL, 0.248mmol), followed by 2-bromoethanol (0.018 mL, 0.248 mmol). The mixturewas left to stir at rt overnight. The reaction mixture was concentratedin vacuo. The residue was dissolved in 1:1 MeOH:DMSO 1 mL and purifiedby MDAP (HpH). The solvent was evaporated in vacuo to give the requiredproduct (14.3 mg, 0.030 mmol, 25%). LCMS (2 min Formic): Rt=0.61 min,[MH]⁺=448.

Example 579:1-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazin-2-one

A solution of tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxopiperazine-1-carboxylate(for a preparation see Intermediate 379, 40 mg, 0.077 mmol) and 4M HClin dioxane (1 ml, 4.00 mmol) in 1,4-dioxane (1 mL) was stirred in aclosed vessel at rt for 20 h. The reaction mixture was concentratedunder a stream of nitrogen and the material was dissolved in MeOH (2mL). This solution was applied to a 2 g SCX cartridge which had beenpre-equilibrated with MeOH (2 mL). The cartridge was washed with MeOH (4mL) and NH₃ in MeOH (2M, 4 mL). The ammonia wash was concentrated invacuo to afford the product (23 mg, 0.055 mmol, 71%). LCMS (2 minFormic): Rt=0.54 min, [MH]⁺=421.

Example 580:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-(piperazin-1-yl)-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A flask containing tert-butyl4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carboxylate(for a preparation see Intermediate 380, 16.1 mg, 0.032 mmol) wasevacuated and back-filled with nitrogen. The sample was dissolved indichloromethane (DCM) (1 mL), and then to this solution was addedtrifluoroacetic acid (0.25 mL, 3.24 mmol). The mixture was stirred at rtunder nitrogen for 30 min. The reaction mixture was concentrated invacuo. The residue was taken up in methanol and loaded onto a 2 g SCX-2SPE cartridge, which had been pre-wet with methanol. The column waswashed with methanol, and then the product was eluted with a 2M solutionof ammonia in methanol. The appropriate fractions were collected andconcentrated in vacuo. The residue was dissolved in 1:1 MeOH:DMSO 1 mLand purified by MDAP (Hph). The solvent was evaporated in vacuo to givethe required product (8.1 mg).

LCMS (2 min HpH): Rt=0.73 min, [MH]⁺=407.

Example 581:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-6-(1H-pyrazol-4-yl)-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

1-((2S,3R,4R)-6-bromo-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 371, 106 mg, 0.264 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate,potassium carbonate (110 mg, 0.792 mmol) and PdCl₂P(Ph₃)₂ (37 mg, 0.053mmol) were combined in a mixture of 1,4-dioxane (3 mL) and water (1 mL)and heated in the microwave reactor at 120° C. for 40 min. The reactionmixture was diluted with ethyl acetate and water. The organic layer wasseparated, washed with water, dried (Na₂SO₄) and concentrated to give˜159 mg of crude yellow residue. This was purified by chromatography onSiO₂ (25 g) eluting with 0-10% methanol/DCM over 330 mL to give amixture of products. Fractions containing desired product were combinedto give 126 mg of crude yellow oil. This was re-purified bychromatography on SiO₂ (25 g) eluting with 0-100% ethylacetate/cyclohexane over 330 mL then 100% ethyl acetate to elute thedesired product to give the product (36 mg, 0.093 mmol, 35%) as a whitesolid.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=389.

Example 582:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

The1-((2S,3R,4R)-6-(1-benzyl-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 383, 133 mg, 0.270 mmol) was takenup in ethanol (10 mL), treated with 10% Pd/C (13 mg, 0.012 mmol) andallowed to stir under a atmosphere of hydrogen for 17 h—no reaction. Thereaction was filtered through celite to remove the catalyst and thefiltrate concentrated to give a colourless oil. This oil was taken up inEtOH (5 mL) and was hydrogenated using the H-cube (settings: 50° C., 20bar, 1 mL/min flow rate) and 10% Pd/C CatCart 30 as the catalyst. Thecompound was cycled through the H-cube for 3 h—no reaction. The reactionwas concentrated to a gum. This gum was re-dissolved in ethanol (10 mL)and treated with formic acid (1 ml, 26.1 mmol) and 10% Pd/C (13 mg,0.012 mmol) and allowed to stir at 80° C. for 4 days. The reaction wasfiltered through celite to remove the catalyst and the filtrateconcentrated and dried to give a yellow oil. This oil was purified usinga MDAP (Formic). The appropriate fractions were summed and concentratedto give the product (13 mg, 0.032 mmol, 12%) as a white solid. LCMS (2min Formic): Rt=0.75 min, [MH]⁺=403.

Example 583:1-((2S,3R,4R)-2-cyclopropyl-6-methoxy-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-methoxy-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 386, 122 mg, 0.445 mmol), 18-crown-6(58.6 mg, 0.222 mmol), potassium fluoride (38.6 mg, 0.665 mmol),2-fluoropyrimidine (48.0 mg, 0.489 mmol) and DIPEA (0.132 mL, 0.756mmol) was suspended in anhydrous DMSO (1 mL). The mixture was stirredunder nitrogen at 140° C. for 16 h. The reaction was allowed to cool tort, diluted with water (5 mL) and extracted with EtOAc (3×5 mL). Theorganic layers were combined, washed with brine (5 mL) and dried over ahydrophobic frit. The solvent was evaporated in vacuo to give a brownsolid. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified byMDAP (HpH). The solvent was evaporated in vacuo to give the requiredproduct (5 mg) as a brown solid.

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=353.

Example 584:1-((2S,3R,4R)-2-cyclopropyl-6-hydroxy-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-2-cyclopropyl-6-methoxy-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 583, 210.4 mg, 0.597 mmol) indichloromethane (DCM) (5 mL) was cooled to 0° C. and put under nitrogen.Boron tribromide (1M in DCM) (0.071 mL, 0.746 mmol) was added to themixture and the reaction left at rt for 16 h. Further boron tribromide(1M in DCM) (0.566 mL, 5.99 mmol) was added at 0° C. and the mixtureleft to stir at rt for 16 h. Ice and ethyl acetate (20 mL) were addedand the solution was washed with water (15 mL) and sat. Na₂CO₃ (15 mL).The organic layer was dried through a hydrophobic frit and evaporated invacuo to give the crude product as a brown oil. The sample was dissolvedin 1:1 MeOH:DMSO 1 mL and purified by MDAP (HpH). The solvent wasevaporated in vacuo to give the required product (54.3 mg) as a whitesolid. LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=339.

Example 585:1-((2S,3R,4R)-2-cyclopropyl-6-(2-hydroxyethoxy)-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

1-((2S,3R,4R)-2-cyclopropyl-6-hydroxy-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Example 584, 20 mg, 0.059 mmol) was dissolved inN,N-dimethylformamide (DMF) (0.6 mL) and treated with 2-bromoethanol(4.54 μL, 0.064 mmol) and potassium carbonate (10 mg, 0.072 mmol). Theheterogeneous mixture was stirred at 100° C. for 2.5 days. The reactionwas incomplete so further 2-bromoethanol (4.54 μL, 0.064 mmol) was addedand heating was continued for a further 5 h. The solvent was removedunder reduced pressure. The residue was dissolved in 1:1 DMSO/MeCN andpurification was undertaken using MDAP (Formic). The collected fractionswere concentrated in vacuo to leave the desired product as a white solid(15 mg). LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=383.

Example 586:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 387, 100 mg, 0.409 mmol),2-fluoropyrimidine (48.2 mg, 0.491 mmol) and DIPEA (0.143 mL, 0.819mmol) in anhydrous dimethyl sulfoxide (DMSO) (2 mL) was heated at 140°C. for 19 h under nitrogen. The reaction mixture was diluted with EtOAc(10 mL) and washed with saturated sodium bicarbonate (2×10 mL) beforebeing dried with anhydrous Na₂SO₄. The filtrate was evaporated in vacuoto give the crude product (141 mg) as an orange oil. The residue wasloaded on a 25 g SNAP silica cartridge in DCM, purified by columnchromatography, eluting with:0-100% EtOAc in cyclohexane (10 CV). Theappropriate fractions were combined and evaporated in vacuo to give therequired product as a yellow oil (69 mg). The sample was dissolved in1:1 MeOH:DMSO 1 mL and purified by MDAP (Formic). The solvent wasevaporated in vacuo to give the required product (39 mg). LCMS (2 minFormic): Rt=0.85 min, [MH]⁺=323.

Example 587:1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 387, 0.3 g, 1.228mmol), 2-bromo-6-methylpyridine (0.280 mL, 2.456 mmol), DavePhos (0.048g, 0.123 mmol), Pd₂(dba)₃ (0.112 g, 0.123 mmol) and sodium tert-butoxide(0.236 g, 2.456 mmol) in 1,4-dioxane (8 mL) was heated under nitrogen at100° C. for 2 h. The reaction was stopped after 80 mins and left overthe weekend. The reaction mixture was then heated to 100° C. for 4 h.Next, further amounts of 2-bromo-6-methylpyridine (0.280 mL, 2.456mmol), DavePhos (0.048 g, 0.123 mmol), Pd₂(dba)₃ (0.169 g, 0.184 mmol)and sodium tert-butoxide (0.307 g, 3.19 mmol) were added and thereaction was heated to 100° C., with stirring, under nitrogen for 30 h.The mixture was allowed to cool to rt and was filtered through a 10 gcelite cartridge, washing with ethyl Acetate (3×20 mL). The combinedfiltrate (dark brown/red) was evaporated in vacuo and the residue wasloaded on a 25 g silica cartridge in DCM, purified by columnchromatography, eluting with: 0-50% EtOAc/DCM (10 CV). The appropriatefractions were combined and evaporated in vacuo to give the crudeproduct as an orange residue, 140 mg. The sample was dissolved in 1:1MeOH:DMSO (3×1 mL injections) and purified by MDAP (Formic). Theappropriate fractions were combined and the solvent was evaporated invacuo to give the required product as the formic acid salt (111 mg). Thesample was loaded in methanol and purified by sulphonic acid SPE (SCX) 2g using sequential solvents methanol, 2M ammonia/methanol. Theappropriate fractions were combined and evaporated in vacuo to give therequired product as the free base as a colourless oil. The oil wasredissolved in MeOH and then evaporated in the blowdown unit beforebeing dried further in the vacuum oven. The product was freeze dried togive the desired product (68 mg, 0.203 mmol, 17%). LCMS (2 min Formic):Rt=0.66 min, [MH]⁺=336.

Example 588:1-((2S,3R,4R)-2-cyclopropyl-6-(1H-imidazol-2-yl)-3-methyl-4-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 388, 51 mg, 0.114 mmol),2-bromo-1H-imidazole (33.4 mg, 0.227 mmol), potassium carbonate (47.2mg, 0.341 mmol) and PdCl₂(PPh₃)₂ (15.97 mg, 0.023 mmol) were combined ina mixture of 1,4-dioxane (2 mL) and water (0.667 mL) and heated in themicrowave reactor at 120° C. for 1 h. The reaction mixture was dilutedwith EtOAc (25 mL) and water (25 mL). The mixture was run through a 2.5g celite cartridge and the layers were separated. The aqueous phase waswashed with EtOAc (2×25 mL). The organic extracts were dried by passingthrough a hydrophobic frit and the solvent evaporated in vacuo to givethe crude (86 mg). Purification was undertaken by flash columnchromatography. The crude material was loaded onto a 10 g silica columnand eluted using a graduating solvent system of 0-15% methanol in DCM.Appropriate fractions were combined and the solvent removed in vacuo togive the product (15.5 mg) as a clear oil.

LCMS (2 min Formic): Rt=0.56 min, [MH]⁺=389.

The following examples were prepared in a similar manner to Example 588using PdCl₂(PPh₃)₂ and K₂CO₃ to couple the appropriate heteroaryl halidewith Intermediate 388.

Rt (mins) Mass Yield (LCMS Ex No. Name Structure (mg) (%) [MH]⁺ method)589 1-((2S,3R,4R)-2- cyclopropyl-3- methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)- 4-(pyrimidin-2- ylamino)-3,4- dihydroquinolin-1(2H)-yl)ethanone

24 50 405 0.78 (2 min Formic) 590 1-((2S,3R,4R)-2- cyclopropyl-3-methyl-6-(5-methyl- 1,3,4-thiadiazol-2-yl)- 4-(pyrimidin-2-ylamino)-3,4- dihydroquinolin- 1(2H)-yl)ethanone

31 65 421 0.82 (2 min Formic)

Example 591:rac-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-3-yl)methylacetate

Acetyl chloride (0.300 mL, 4.22 mmol) was added drop-wise to a solutionofrac-((2S,3S,4R)-2-cyclopropyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-3-yl)methanol(for a preparation see Intermediate 390, 591 mg, 2.008 mmol) and DIPEA(1.052 mL, 6.02 mmol) in dichloromethane (DCM) (10 mL). The resultingsolution was stirred for 1 h. The reaction mixture was evaporated invacuo to a yellow oil. The residue was dissolved in DCM, loaded on to a25 g silica column and eluted with cyclohexane:EtOAc (5-25%). Theproduct containing fractions were evaporated in vacuo to a white solid(549 mg). LCMS (2 min TFA): Rt=1.12 min, [MH]⁺=379.

Example 592:rac-1-((2S,3R,4R)-2-cyclopropyl-3-(hydroxymethyl)-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Potassium carbonate (203 mg, 1.468 mmol) was added to a solution ofrac-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-3-yl)methylacetate (for a preparation see Example 591, 505 mg, 1.334 mmol) in amixture of tetrahydrofuran (THF) (5 mL), methanol (10 mL) and water (1mL) at 60° C. The resulting suspension was stirred for 3 h and allowedto stand over the weekend. The reaction mixture was partitioned betweenEtOAc and water. The aqueous layer was removed and the organic layerwashed (1× brine), dried over MgSO₄ and evaporated in vacuo to acolourless oil. The residue was dissolved in DCM, loaded on to a 25 gsilica column and eluted with cyclohexane:EtOAc (5-50%). The productcontaining fractions were evaporated to give the product as a whitesolid (203 mg). LCMS (2 min TFA): Rt=1.03 min, [MH]⁺=337.

Example 593:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution ofrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 394, 82 mg, 0.200 mmol) inN,N-dimethylformamide (DMF) (1.5 mL) was added HATU (84 mg, 0.220 mmol)followed by DIPEA (0.070 ml, 0.400 mmol). The resulting reaction mixturewas stirred at rt under N₂ for 15 min. Ammonium chloride (21.37 mg,0.400 mmol) was then added and the reaction stirred for ˜1 h. Thereaction mixture was diluted to 1.8 mL and separated equally between 2vials. The vials were purified by MDAP (HpH), the appropriate fractionswere collected and concentrated in vacuo to afford the desired productas a cream glass (64 mg, 0.156 mmol, 78%).

LCMS (2 min Formic): Rt=0.67 min, [MH]⁺=410.

Example 594:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-hydroxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution ofrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-methoxy-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide(for a preparation see Example 593, 20 mg, 0.049 mmol) indichloromethane (DCM) (1 mL) at 0° C. was added boron tribromide (1M indichloromethane) (0.488 mL, 0.488 mmol). A suspension immediatelyformed. The resulting reaction mixture was stirred at rt under N₂ for 74h, during which time the solvent evaporated. The reaction was dilutedwith DCM and methanol (0.198 mL, 4.88 mmol) and the resultant solutionconcentrated in vacuo. Further methanol (0.198 mL, 4.88 mmol) was addedand the sample evaporated in vacuo once again. The resultant solid wastaken up in DCM with a small amount of MeOH and added to a silica (10 g)column and purified by flash column purification, eluting with 0->25%(20% MeOH/DCM)/DCM. A close eluting impurity was observed, therefore thepurest fractions were collected and concentrated in vacuo to afford thedesired product as a white gum (6.1 mg, 0.015 mmol, 32%). LCMS (2 minFormic): Rt=0.70 min, [MH]⁺=396.

Example 595:(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide

To a solution of(2S,3R,4R)-1-acetyl-2-cyclopropyl-7-fluoro-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (for a preparation see Intermediate 399, 19.7 mg, 0.049 mmol) inN,N-Dimethylformamide (DMF) (0.7 ml) was added HATU (28.2 mg, 0.074mmol) followed by DIPEA (0.026 ml, 0.148 mmol). The resulting reactionmixture was stirred at r.t. under N2 for 15 min. ammonium chloride (7.93mg, 0.148 mmol) was then added and the reaction stirred for ˜1 h. Thereaction mixture was purified directly by MDAP (HpH) to afford acolourless oil (15.2 mg, 0.038 mmol, 77%). LCMS (2 min Formic): Rt=0.75min, [MH]⁺=399.

Examples 596a & 596b:1-((2R,3S,4S)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(596a) &1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(596b)

rac-1-((2S,3R,4R)-2-ethyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 407, ˜18 mg) was submitted forchiral separation into its enantiomers (A and B) using a 250×20 mmChiralpak AS column eluting with 20% ethanol in 80% heptane at a flowrate of 20 mL/min. Peak 1/Enantiomer A fractions were collected between4 and 6 min. Peak 2/Enantiomer B fractions were collected between 6 and10 min. Fraction solutions were combined then evaporated to dryness togive Enantiomer A (11 mg) and Enantiomer B (11 mg) as white solids.

Enantiomer A, Example 596a

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak AS column elutingwith 20% ethanol in heptane at 1 mL/min—Rt=4.6 min. 97% ee by UV.

Enantiomer B, Example 596b

Analytical Chiral HPLC using a 250×4.6 mm Chiralpak IC column elutingwith 20% ethanol in heptane at 1 mL/min—Rt=7.6 min, >99% ee by UV.

Example 597:rac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxamide

HATU (118 mg, 0.310 mmol), DIPEA (0.226 mL, 1.293 mmol) and ammoniumchloride (41.5 mg, 0.776 mmol) were added to a solution ofrac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylicacid (for a preparation see Intermediate 413, 95 mg, 0.259 mmol) inN,N-dimethylformamide (DMF) (5 mL). The reaction mixture was stirred atrt for 3 h. The reaction mixture was concentrated under reduced pressureto give a green a residue (285 mg). The residue was loaded on a 25 gsilica cartridge, purified by column chromatography, eluting with 0-8%NH₃ (2M in MeOH) in DCM (20 CV). The appropriate fractions were combinedand concentrated under reduced pressure to give the crude product (128mg). The residue was taken up in 1:1 MeOH:DMSO (2×1 mL) and purified byMDAP (HpH). The solvent was evaporated in vacuo to give the requiredproduct (55 mg) as a yellow-white solid.

LCMS (2 min HpH): Rt=0.71 min, [MH]⁺=367.

Example 598a & 598b:rac-1-((2S,3R,4R)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(598a) & rac-1-((2,3,4unknown)-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)ethanone(598b)

Therac-(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-yltrifluoromethanesulfonate compound with(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yltrifluoromethanesulfonate (1:1) (for a preparation see Intermediate 419,130 mg, 0.134 mmol) was taken up in N,N-dimethylformamide (DMF) (5 mL)and was treated with PdCl₂(dppf) (19.59 mg, 0.027 mmol), triethylamine(0.075 mL, 0.536 mmol) and formic acid (0.021 mL, 0.536 mmol) thereaction was allowed to stir at 60° C. under nitrogen for 16 h. Thereaction was treated with further PdCl₂(dppf) (19.59 mg, 0.027 mmol) andformic acid (0.021 mL, 0.536 mmol) and allowed to stir at 60° C. undernitrogen for 3 days. The reaction was allowed to cool to rt and wasapplied directly to a pre-conditioned (MeOH) SCX SPE (5 g) elute: MeOHand 2M NH₃/MeOH the ammonia fraction was concentrated to a brown oil,this oil was purified using a MDAP (HpH). Two main peaks were collected;the appropriate fractions were summed and concentrated to give what wasbelieved to be the desired product (Example 598a, 1^(st) eluting isomer)(11 mg) & a second product (Example 598b 2^(nd) eluting isomer) whichhad an unknown but alternative relative stereochemistry (16 mg).

Isomer 1: LCMS (2 min Formic): Rt=0.60 min, [MH]⁺=338.

Isomer 2: LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=338.

Example 599:rac-1-((2S,3S,4R)-2-cyclopropyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Bromobenzene (0.037 mL, 0.356 mmol) and sodium tert-butoxide (52.5 mg,0.546 mmol) were added to a solution ofrac-1-((2S,3S,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(for a preparation see Intermediate 422, 58 mg, 0.237 mmol) in toluene(3 mL). The resulting solution was vacuum degassed under N₂, Pd(QPhos)₂(18.13 mg, 0.012 mmol) added, the reaction vacuum degassed under N₂ andheated to 50° C. under N₂ for 4 h. The reaction was cooled to rt, loadeddirectly on to a 10 g silica column and eluted with cyclohexane:EtOAc(0-25%). The product containing fractions were evaporated in vacuo to apale brown solid (48 mg).

LCMS (2 min TFA): Rt=1.19 min, [MH]⁺=321.

Biological Test Methods

The compounds of formula (I) may be tested in one or more of thefollowing assays:

Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay

Binding was assessed using a time resolved fluorescent resonance energytransfer binding assay. This utilises a 6 His purification tag at theN-terminal of the proteins as an epitope for an anti-6 His antibodylabeled with Europium chelate (PerkinElmer AD0111) allowing binding ofthe Europium to the proteins which acts as the donor fluorophore. Asmall molecule, high affinity binder of the bromodomains BRD2, BRD3,BRD4 and BRDT has been labeled with Alexa Fluor647 (Reference CompoundX) and this acts as the acceptor in the FRET pair.

Reference Compound X:4-((Z)-3-(6-((5-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)pentyl)amino)-6-oxohexyl)-2-((2E,4E)-5-(3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indol-1-ium-2-yl)penta-2,4-dien-1-ylidene)-3-methyl-5-sulfoindolin-1-yl)butane-1-sulphonate)

To a solution ofN-(5-aminopentyl)-2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide(for a preparation see Reference Compound J, WO2011/054848A1, 1.7 mg,3.53 μmol) in DMF (40 μl) was added a solution of AlexaFluor647-ONSu(2.16 mg, 1.966 μmol) also in DMF (100 μl). The mixture was basifiedwith DIPEA (1 μl, 5.73 μmol) and agitated overnight on a vortex mixer.

The reaction mixture was evaporated to dryness. The solid was dissolvedin acetonitrile/water/acetic acid (5/4/1, <1 ml) filtered and wasapplied to a Phenomenex Jupiter C18 preparative column and eluted withthe following gradient (A=0.1% trifluoroacetic acid in water, B=0.1%TFA/90% acetonitrile/10% water): Flow rate=10 ml/min., AU=20/10 (214nm):

5-35%, t=0 min: B=5%; t=10 min: B=5%; t=100 min: B=35%; t=115 min:B=100% (Sep. grad: 0.33%/min)

The major component was eluted over the range 26-28% B but appeared tobe composed of two peaks. The middle fraction (F1.26) which shouldcontain “both” components was analysed by analytical HPLC (SpherisorbODS2, 1 to 35% over 60 min): single component eluting at 28% B.Fractions F1.25/26&27 were combined and evaporated to dryness.Transferred with DMF, evaporated to dryness, triturated with dry etherand the blue solid dried overnight at <0.2 mbar: 1.54 mg.

Analytical HPLC (Sphersisorb ODS2, 1 to 35% B over 60 min): MSM10520-1:[M+H]⁺ (obs): 661.8/− corresponding with M-29. This equates to[(M+2H)/2]⁺ for a calculated mass of 1320.984 which is M-29. This is astandard occurrence with the Alexa Fluor 647 dye and represents atheoretical loss of two methylene groups under the conditions of themass spectrometer.

Assay Principle: In the absence of a competing compound, excitation ofthe Europium causes the donor to emit at λ618 nm which excites the Alexalabelled bromodomain binding compound leading to an increased energytransfer that is measurable at λ647 nM. In the presence of a sufficientconcentration of a compound that can bind these proteins, theinteraction is disrupted leading to a quantifiable drop in fluorescentresonance energy transfer.

The binding of the compounds of formula (I) to Bromodomains BRD2, BRD3,BRD4 and BRDT was assessed using mutated proteins to detect differentialbinding to either Binding Domain 1 (BD1) or Binding Domain 2 (BD2) onthe bromodomain. These single residue mutations in the acetyl lysinebinding pocket greatly lower the affinity of the fluoroligand (ReferenceCompound X) for the mutated domain (>1000 fold selective for thenon-mutated domain). Therefore in the final assay conditions, binding ofthe fluoroligand to the mutated domain cannot be detected andsubsequently the assay is suitable to determine the binding of compoundsto the single non-mutated bromodomain.

Protein production: Recombinant Human Bromodomains [(BRD2 (1-473)(Y113A) and (Y386A), BRD3 (1-435) (Y73A) and (Y348A) BRD4 (1-477) (Y97A)and (Y390A) and BRDT (1-397) (Y66A) and (Y309A)] were expressed in E.coli cells (in pET15b vector for BRD2/3/4 and in pET28a vector for BRDT)with a 6-His tag at the N-terminal. The His-tagged Bromodomain pelletwas resuspended in 50 mM HEPES (pH7.5), 300 mM NaCl, 10 mM imidazole & 1μl/ml protease inhibitor cocktail and extracted from the E. coli cellsusing sonication and purified using a nickel sepharose high performancecolumn, the proteins were washed and then eluted with a linear gradientof 0-500 mM imidazole with buffer 50 mM HEPES (pH7.5), 150 mM NaCl, 500mM imidazole, over 20 column volumes. Final purification was completedby Superdex 200 prep grade size exclusion column. Purified protein wasstored at −80° C. in 20 mM HEPES pH 7.5 and 100 mM NaCl. Proteinidentity was confirmed by peptide mass fingerprinting and predictedmolecular weight confirmed by mass spectrometry.

Protocol for Bromodomain BRD2, 3, 4 and T, BD1+BD2 mutant assays: Allassay components were dissolved in buffer composition of 50 mM HEPESpH7.4, 50 mM NaCl, 5% Glycerol, 1 mM DTT and 1 mM CHAPS. The finalconcentration of bromodomain proteins were 10 nM and the Alexa Fluor647ligand was at Kd. These components were premixed and 5 μl of thisreaction mixture was added to all wells containing 50 nl of variousconcentrations of test compound or DMSO vehicle (0.5% DMSO final) inGreiner 384 well black low volume microtitre plates and incubated indark for 30 minutes at rt. 5 μl of detection mixture containing 1.5 nMfinal concentration anti-6His Europium chelate was added to all wellsand a further dark incubation of at least 30 minutes was performed.Plates were then read on the Envision platereader, (λex=317 nm, donorλem=615 nm; acceptor λem=665 nm; Dichroic LANCE dual). Time resolvedfluorescent intensity measurements were made at both emissionwavelengths and the ratio of acceptor/donor was calculated and used fordata analysis. All data was normalized to the mean of 16 high (inhibitorcontrol—Example 11 of WO 2011/054846A1) and 16 low (DMSO) control wellson each plate. A four parameter curve fit of the following form was thenapplied:

y=a+((b−a)(1+(10{circumflex over ( )}x/10{circumflex over( )}c){circumflex over ( )}d)

Where ‘a’ is the minimum, ‘b’ is the Hill slope, ‘c’ is the pIC₅₀ and‘d’ is the maximum.

All compounds (Examples 1-599), with the exception of Examples 122, 135and 137, were each tested in the BRD4 BD1 and the BRD4 BD2 TR-FRETassays described above.

All tested compounds were found to have a pIC₅₀≥4.0 in at least oneassay.

Examples 23, 25b, 27b, 29b, 48, 49, 50, 53, 54, 65, 67, 68, 71a, 91b,102b, 107-113, 114b, 127, 138b, 146b, 147a, 183, 187, 188, 189b, 210,211, 218, 220, 221, 227, 228, 239b, 298, 316, 332, 348, 387, 391, 397,408, 422, 441, 503, 517, 519, 522, 531, 532, 533, 551a, 591, 592, 593,596b, and 598b were found to have a pIC₅₀≥4.0 and <6.0 in the BRD4 BD2assay.

All other tested compounds were found to have a pIC₅₀≥6.0 in the BRD4BD2 assay.

Examples 1-9, 12, 13, 15, 16, 20, 22, 25a, 27a, 29a, 30, 32, 57-60, 62,69, 70, 71b, 72, 74, 77, 80, 81, 85, 87, 91a, 92, 94, 97-99, 115, 119,124, 134, 136a, 138a, 139, 141, 143, 146a, 147b,150,161,166-169,177,181, 189a, 192, 197, 214, 230, 231,235,237,239a,240, 243, 248, 249, 252-254, 256, 261, 262, 265-267, 269-274, 279, 283,285, 291, 300-304, 306-311, 314, 318, 320-323, 331, 337-341, 350,352-357, 359, 360, 362-365, 367-375, 378, 379, 381-384, 390, 392,394-396, 399, 400, 403, 407, 411, 413, 418, 424-426, 430, 433, 436-440,443-448, 451b, 452-467, 469, 471, 473-476, 479, 480, 484, 488, 489, 492,493, 495-498, 501, 504, 506, 509, 518, 523, 527, 528, 540-542, 545-548,555, 557, 559-566, 571, 575-578, 581, 582, 588 and 590 were found tohave a pIC₅₀≥7.0 in the BRD4 BD2 assay.

Calculation of Selectivity for BRD4 BD2 Over BRD4 BD1

Selectivity for BRD4 BD2 over BRD4 BD1 was calculated as follows:

Selectivity=BRD4 BD2 pIC₅₀−BRD4 BD1 pIC₅₀

pIC₅₀ values are expressed as log₁₀ units.

With the exception of Examples 23, 24, 25b, 27b, 29b, 71a, 83, 91b,102b, 112, 114b, 127, 138b, 140, 142, 143, 147a, 154, 166, 167, 169,173, 174, 180, 183, 189b, 200, 202, 213, 217, 221, 230, 232, 233, 236,237, 239b, 242, 332, 348, 397, 404, 412, 415, 422, 430, 440, 442, 460,462, 466, 517, 532, 533, 541, 542, 544, 548, 551a, 552, 554, 591, 596band 598b) all tested compounds were found to have selectivity for BRD4BD1 over BRD4 BD2 of ≥1 log unit in at least one of the TR-FRET assaysdescribed above, hence are at least 10 fold selective for BRD4 BD2 overBRD4 BD1

Examples 3, 25a, 26, 27a, 28, 29a, 30-37, 55-57, 61, 63, 64, 66, 85-90,91a, 92-96, 102a, 116, 117, 119, 124, 133, 136a, 146a, 152, 158, 161,162, 164, 189a, 191, 192, 204, 207, 223, 224, 235, 238, 243, 245,248-251-263, 279, 280, 281, 286, 287, 289, 290, 296, 297, 301-309, 312,315, 318-323, 326, 337, 339, 340, 350-353, 357-360, 363, 364, 367, 368a,368b, 371, 374, 375, 378, 382, 390, 392, 393, 416, 419, 421, 424-426,432, 438, 480, 481, 492-496, 499, 512, 513, 516, 520, 523, 524, 539,586, and 587 were found to have selectivity for BRD4 BD1 over BRD4 BD2of 2 log unit in at least one of the TR-FRET assays described above,hence are at least 100 fold selective for BRD4 BD2 over BRD4 BD1.

1-45. (canceled)
 46. A method for the preparation of a compound offormula I comprising a step of reacting a compound of formula II with acompound of formula VIII:

wherein: R₁ is C₁₋₄alkyl; R₂ is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CH₂CF₃,—CH₂OCH₃ or heterocyclyl; R₃ is C₁₋₄alkyl, —CH₂F, —CH₂OH or—CH₂OC(O)CH₃; R₄ when present is H, hydroxy, halo, cyano, —CO₂H, —CONH₂,—OSO₂CF₃, —C(O)N(R₈)C₁₋₄ alkyleneOH, —C(O)N(R₈)C₁₋₄alkyleneOCH₃,—C(O)N(R₈)C₁₋₄alkyleneNR₆R₇, —C(O)N(R₈)C₁₋₄alkyleneSO₂CH₃,—C(O)N(R₈)C₁₋₄alkyleneCN, —C(O)NHOH, —C(O)NHCH(CH₂OH)₂, —OCH₂CH₂OH,—B—C₁₋₆alkyl, —B—C₃₋₇cycloalkyl, —B-phenyl, —B-heterocyclyl or—B-heteroaromatic, wherein the C₃₋₇cycloalkyl, phenyl, heterocyclyl orheteroaromatic ring is optionally substituted by 1 or 2 substituentsindependently selected from ═O, C₁₋₆alkyl, C₁₋₆alkoxy, halo, —NH₂,—CO₂H, —C(O)C₁₋₆alkyl, —C(O)NHC₁₋₆alkyl, cyano, —CH₂CH₂NHCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, C₃₋₇cycloalkyl, phenyl, heterocyclyl and heteroaromatic; R₅when present is H, halo, hydroxy or C₁₋₆alkoxy; A is —NH—; B is a bond,—O—, —N(R₈)—, S, —SO—, —SO₂—, —SO₂N(R₈)—, —CH₂—, —C(O)—, —CO₂—,—N(R₈)C(O)—, —C(O)N(R₈)—, —C(O)N(R₈)CH₂— or —C(O)N(R₈)CH₂CH₂—; V isphenyl, heteroaromatic or pyridone any of which may be optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₆alkyl, fluorine, chlorine, C₁₋₆alkoxy, hydroxy, cyclopropyl, cyano,—CO₂CH₃, heterocyclyl, —CO₂H, —CH₂NR₆R₇, —NR₆R₇, —C(O)NR₆R₇, —NR₆C(O)R₇,—CF₃, —NO₂, —CH₂OCH₃, —CH₂OH, —CH(OH)CH₃, —SO₂CH₃, —CH₂heterocyclyl,—OCH₂CH₂NHC(O)CH₃, —OCH₂CH₂OH, —OCH₂CH₂NH₂, —C(O)NHheteroaromatic,—C(O)NHCH₂heterocyclyl, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂CH₂NH₂,—C(O)NHCH₂CH₂SO₂Me, —C(O)NHCH₂CH(OH)CH₃, —C(O)heterocyclyl and—C(O)NHheterocyclyl, wherein the heterocyclyl ring is optionallysubstituted by —OH; R₆, R₇, R₈ are each independently selected from Hand C₁₋₄alkyl; W is CH or N; X is C or N; Y is C or N; and Z is CH or N;Hal is fluorine, chlorine, bromine or iodine; subject to the provisothat no more than 2 of W, X, Y and Z are N; and that the compound offormula (I) is not1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanoneor1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one.47. The method of claim 46, further comprising the step of preparing acompound of formula (II) comprising hydrogenation of a compound offormula (III)

wherein R₁₀ is selected from benzyl or t-butyl.
 48. The method of claim47, further comprising the step of preparing a compound of formula(III), wherein R₃ is methyl and R₁₀ is benzyl, comprising reacting acompound of formula (IV) with a compound of formula (IX):


49. The method of claim 48, wherein the reaction between the compound offormula IV and the compound of formula IX is carried out in the presenceof a suitable base.
 50. The method of claim 49, wherein the suitablebase is pyridine or DIPEA.
 51. The method of claim 48, furthercomprising the step of preparing a compound of formula IV comprisingreacting a compound of formula V with a compound of formula VII and acompound of formula X:


52. The method of claim 51, wherein the reaction is carried out in thepresence of an acid catalyst.
 53. The method of claim 52, wherein theacid catalyst is(11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine4-oxide.
 54. The method of claim 51, further comprising the step ofpreparing a compound of formula V comprising oxidation of a compound offormula VI in the presence of an oxidising agent a phosphine ligand:


55. The method of claim 54, wherein the oxidising agent is DIAD and thephosphine ligand is PPh₃.
 56. The method of claim 46, wherein Hal isfluorine.
 57. The method of claim 46, wherein the compound of formula Iis a racemic mixture of formula (Ia)


58. The method of claim 46, wherein the compound of formula (I) is anenantiomer of formula (Iaa)


59. The method of claim 46, wherein R₁ is methyl.
 60. The method ofclaim 46, wherein R₂ is cyclopropyl.
 61. The method of claim 46, whereinR₃ is methyl.
 62. The method of claim 46, wherein R₄ is fluoro, cyano,CO₂H or —CONH₂.
 63. The method of claim 46, wherein R₄ is —CONH₂. 64.The method of claim 46, wherein R₅ is H.
 65. The method of claim 46,wherein V is pyrimidinyl optionally substituted by 1 or 2 C₁₋₆alkylgroups.
 66. The method of claim 46, wherein V is


67. The method of claim 46, wherein W is CH; X is C; Y is C; and Z isCH.
 68. The method of claim 46, wherein the compound of formula (I) is(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide.69. The method of claim 51, wherein R₄ is cyano.
 70. The method of claim51, wherein R₂ is cyclopropyl.
 71. The method of claim 47, wherein R₁₀is benzyl.